Transcranial magnetic stimulation for post‐traumatic stress disorder
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
1) To determine the overall efficacy and tolerability of TMS in the treatment of PTSD.
2) To identify clinical and methodological factors that increase response to treatment with TMS.
Background
Description of the condition
Post traumatic stress disorder (PTSD) is recognised in the latest edition of the Diagnostic and Statistical Manual (APA 2000) as a pathological response to psychological trauma, characterised by intrusive (e.g., flashbacks, nightmares), avoidance/numbing (e.g., loss of interest, detachment) and hyperarousal (e.g., irritability, difficulty concentrating, sleeping) symptoms.
There is evidence that PTSD is associated with substantial reductions in quality of life, a high co‐morbidity of psychiatric and medical disorders, marked functional impairment, and high economic costs (Solomon 1997; Brunello 2001). A nationally representative mental health survey, the National Comorbidity Survey, discovered that between 50 and 60% of people in the United States are exposed to trauma during their lifetime. A recent replication of this survey discovered that as many as 3.5% of those interviewed had PTSD within the previous 12 months (Kessler 2005).
Description of the intervention
Transcranial magnetic stimulation (TMS) is a relatively new neuropsychiatric technique, with the first modern device developed in the mid 1980s (Barker 1985). TMS involves the non‐invasive induction of an electric current in the brain. A current flowing through a coil placed in close proximity to the scalp generates an oscillating magnetic field, that in turn generates a corresponding electrical current within the part of the brain lying under the coil. In adjusting certain stimulation parameters, such as the intensity and frequency of the magnetic field delivered to the brain, investigators can induce excitation or inhibition of neural activity within targeted cortical regions.
Reports of changes in mood in healthy and depressed individuals after the application of both single and repetitive pulses of TMS suggests that TMS may have potential as a treatment intervention (Bickford 1987; Pascual‐Leone 1996; Grunhaus 2000; Schutter 2001). Repetitive TMS (rTMS) has received regulatory approval as a treatment for major depressive disorder in a number of countries, based on the findings of controlled trials of rTMS in treating this condition (as reviewed in Holtzheimer 2001; McNamara 2001; Burt 2002; Kozel 2002). Nevertheless, a number of reviews employing the methodology of the Cochrane Collaboration (Martin 2001, Couturier 2005) concluded that evidence of a benefit from using repetitive transcranial magnetic stimulation to treat depression was lacking. Randomised controlled trials have found the response rates of rTMS to be comparable to that of electroconvulsive therapy (ECT) in treating non‐psychotic depression (Grunhaus 2003; Rosa 2006). Treatment with rTMS, however, is not associated with the adverse cognitive effects of ECT. Indeed, rTMS appears to possess a relatively benign safety profile, with headache and neck pains the most frequently reported complaints in stimulation of those parts of the brain commonly targeted in treating psychiatric disorders (Machii 2006).
There are indications that rTMS might be effective in treating PTSD. Reductions in the severity of PTSD symptoms were observed in a case study of slow rTMS (1Hz) to the right prefrontal cortex (McCann 1998). A single open session of bilateral motor cortex stimulation resulted in a transient reduction in avoidance symptoms and increased treatment response on the CGI‐I within the first 24 hours after treatment (Grisaru 1998). However, biases associated with the designs of these studies limit the strength of the conclusions that can be drawn. In a randomised controlled trial (RCT), 10 sessions of slow (1 Hz) versus fast (10 Hz) rTMS of the right prefrontal cortex compared to a sham control led to significant reductions in symptom severity. A significant reduction of anxiety was also detected in the high frequency intervention. (Cohen 2004). These effects lasted for a full 14 days after treatment.
How the intervention might work
The mechanisms of action for the therapeutic effect of rTMS are unclear. Current technology confines the direct effects of rTMS to the surface of the brain (the cortex), while brain imaging studies have characterised PTSD in terms of the structural and functional pathology of subcortical structures (Bohning 1997; Karl 2006). For instance, numerous studies have detected hyperactivation of the amygdala in PTSD, a subcortical structure implicated in the arousal response to fearful situations and the encoding and consolidation of memories for traumatic events (Rauch 2000; Protopopescu 2005; Shin 2005; Williams 2006). There is evidence that rTMS may exert its effects through stimulating activity in the prefrontal cortex (PFC), which could further inhibit the amydala by means of negative feedback circuitry. When coupled with the inhibition of sympathetic function, deficits in this neural circuit might account for specific symptom clusters observed in PTSD, such as hyperarousal (Cohen 2004).
The inhibitory effects on cortical neurons of low frequency rTMS might also underlie its therapeutic efficacy, given evidence of reduced inhibition of cortical neurons in PTSD patients suffering from minor head trauma (Centonze 2005). Other possible mechanisms of action include changes to activity of the hypothalamus‐pituitary‐adrenal (HPA) axis, a structure that has consistently been implicated in the pathogenesis of PTSD (Yehuda 2002). Animal studies have also demonstrated that TMS affects the dopaminergic and serotonergic neurotransmitter systems in the brain, both of which are known to be involved in the stress response (Ikeda 2005; Kole 1999). Evidence for changes in the serotonergic system following rTMS is particularly pertinent, given evidence for the efficacy of the selective serotonin reuptake inhibitors (SSRIs) in treating PTSD (Stein 2006).
Why it is important to do this review
There are no systematic reviews of rTMS in treating PTSD currently available. Although certain forms of psychotherapy and medication have proven efficacy in the treatment of PTSD, a recent Cochrane review of pharmacotherapy RCTs found that only 59% of people with PTSD responded to SSRIs (Stein 2006). The number who achieve full recovery is likely to be even lower. TMS could therefore be a valuable addition to the treatment strategies currently available for treating PTSD, either in isolation, or in augmenting response to these strategies.
A Cochrane review would help to (a) determine the effectiveness of TMS in treating PTSD, (b) assess the relative efficacy of TMS compared to standard treatments such as medication, psychotherapy and ECT, (c) determine whether the effects of TMS are specific to PTSD, given the high comorbidity between PTSD and major depression, and (d) provide information on the influence of methodological characteristics on treatment response, such as the intensity of stimulation, the positioning of the coil, the duration of treatment, and whether a sham was used as control.
Objectives
1) To determine the overall efficacy and tolerability of TMS in the treatment of PTSD.
2) To identify clinical and methodological factors that increase response to treatment with TMS.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials of repetitive transcranial magnetic stimulation in the treatment of post traumatic stress disorder. Publication is not necessarily related to study quality and indeed publication may imply certain biases (Dickersin 1992; Song 2000), so unpublished abstracts and reports will also be considered. Trial reports in all languages will be included.
Types of participants
All participants diagnosed with PTSD according to the Diagnostic and Statistical Manual (DSM III (APA 1980) or DSM‐IV (APA 1994)), or the International Classification of Diseases (ICD‐9 (WHO 1975) or ICD‐10 (WHO 1992)). No restrictions will be applied in terms of age, gender or race.
Types of interventions
Trials comparing repetitive transcranial magnetic stimulation versus (1) sham rTMS, (2) electroconvulsive therapy, (3) medications, or (4) psychotherapy will be included in the review. In addition, trials comparing high versus low frequency stimulation and placement of the coil above the right versus left dorsolateral prefrontal cortex will also be included.
Interventions consisting of single‐pulse TMS, or rTMS administered in either a single session, or over a period of less than one week will not be included in the review.
Types of outcome measures
Primary outcome measure
The reduction of symptom severity will be determined from the Clinician Administered PTSD Scale (CAPS) (Blake 1990), which has become the "gold standard" measure of treatment efficacy in RCTs of PTSD.
Secondary outcome measures
1) Treatment response (responders versus non‐responders) will be determined from the Clinical Global Impressions scale ‐ Improvement item (CGI‐I) (or closely related measure), a widely used global outcome measure (Guy 1976). Responders are defined on the CGI‐I as those with a score of 1 = "very much" or 2 = "much" improved.
2) Scores on symptom rating scales for disorders other than the primary anxiety disorder, including:
a) Depression symptom severity scales, such as the Hamilton Depression scale (HAM‐D) (Hamilton 1960) and the Montgomery‐Asberg Depression Rating Scale (MADRS) (Montgomery 1979), and
b) Anxiety symptom severity scales, such as the Hamilton Anxiety scale (HAM‐A) (Hamilton 1959).
3) Functional disability, such as the Sheehan Disability Scale (SDS), which includes subscales to assess work, social and family related impairment (Sheehan 1996).
4) Quality of life, such as the SF‐36 Health Survey (Ware 1992).
5) Tolerability of rTMS will be determined by calculating the proportion of participants who withdrew from the interventions due to treatment‐related adverse events. This is included in the analysis as a surrogate measure of treatment acceptability, in the absence of other more direct indicators of acceptability. Acceptability of rTMS will be determined by:
a) a conservative measure of treatment acceptability that includes patient withdrawals due to (1) treatment‐related adverse events, (2) any adverse events, and (3) poor response to treatment.
b) a narrative review of significant differences between the treatment and control groups in the prevalence of the most common adverse events (defined as occurring in at least 20% of the participants given rTMS, on the basis of the typically small sample sizes employed) for both trials included and excluded from the quantitative analyses.
Search methods for identification of studies
Electronic Searches
1) The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers [CCDANCTR‐Studies and CCDANCTR‐References] will be searched using the following search strategies.
CCDANCTR‐Studies
Diagnosis = "Post‐Traumatic Stress Disorders"
and
Intervention = "Magnetic Stimulation"
CCDANCTR‐References
Keyword = "Post Trauma*" or "Posttrauma*" or "Post‐Trauma*" or "Stress Disorder*" or "Stress‐Disorder*"
or
Free‐text = Acute Stress" or "Trauma* Stress" or PTSD
and
Free‐text = TMS or RTMS or "Magnetic Stimulation"
2) Additional searches will be conducted using MEDLINE (via PubMed, 1966 ‐ July 2007), and PsycINFO (1972‐2007 PART B).
The complete MEDLINE search query, as derived from the search strategy developed by Robinson 2002, is provided below:
(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ("latin square" [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow‐up studies [mh] OR prospective studies [mh] OR cross‐over studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animal [mh] NOT human [mh]) AND ((transcranial Magnetic Stimulation [mh] OR "transcranial Magnetic stimulation" OR "rTMS" OR "TMS") AND (Stress Disorders, Post‐Traumatic [mh:noexp] OR "posttraumatic stress disorder" [tw] OR "post traumatic stress disorder" [tw] OR PTSD [tw]))
PsycINFO will be searched using the following query: ("randomi*" or "controlled") and ("transcranial magnetic stimulation" or "rTMS" or "TMS") and ("PTSD" or "post‐traumatic stress disorder" or "posttraumatic stress disorder"). PsycINFO includes the Dissertational Abstracts International database ‐ a database of unpublished dissertations.
3) Ongoing trials will be located using the metaRegister of Controlled Trials database [mRCT]( http://www.controlled‐trials.com) as well as the National Institute of Health's Computer Retrieval of Information on Scientific Projects [CRISP] service (1972‐2006). The search terms "(TMS or rTMS or 'transcranial magnetic stimulation') AND ('PTSD' or 'post‐traumatic stress disorder' or 'posttraumatic stress disorder')" and "(TMS AND PTSD)" will be entered into the search interfaces for these databases, respectively.
Reference Lists
Additional RCTs will be sought in reference lists of the retrieved articles.
Correspondence
1) Attempts will be made to obtain published and unpublished trials from key researchers, as identified by the frequency with which they are cited in the bibliographies of RCTs and open‐label studies.
2) Manufacturers of TMS equipment (Brainsway, MagStim, Neotonus, Nueronetics, Medtronic) will also be contacted for information on published and unpublished studies.
Data collection and analysis
Selection of studies
RCTs identified from the search will be independently assessed for inclusion by two review authors (JI & NP), based on information included in the abstract and/or method section of the trial report. The authors will also independently collate the data listed under "Data extraction and management" from RCTs that they both regard as satisfying the inclusion criteria specified in the "criteria for considering studies" section. Studies that require additional information to determine their suitability for inclusion in the review will be listed in the "studies awaiting assessment" table in the Review Manager (RevMan) software, pending the availability of this information. Any disagreements in the independent trial assessment and data collation procedures will be resolved by discussion with a third author (DS).
Data extraction and management
Spreadsheets will be designed for the purpose of recording descriptive information, summary statistics of the outcome measures, the quality scale ratings, and associated commentary. Once these data have been entered, they will be exported to the Review Manager (RevMan) software, which will be used to conduct the meta‐analysis. Where information is missing, the review authors will contact investigators by e‐mail in an attempt to obtain this information.
The following information will be collated from each trial:
1) Description of the trial, including the primary researcher, the year of publication, and the source of funding.
2) Characteristics of the interventions, including the number of participants randomised to the treatment and control groups, the number of total drop‐outs per group as well as the number that dropped out due to adverse effects, the intensity, frequency and duration of the stimulation, as well as the period over which it was administered.
3) Characteristics of trial methodology, including the diagnostic (e.g.. DSM‐IV (APA 1994)) and exclusionary criteria employed, the screening instrument used (e.g., the Structured Clinical Interview for DSM‐IV (SCID) (Spitzer 1996)) for both the primary and comorbid diagnoses, the presence of comorbid major depressive disorder (MDD), the use of a placebo run‐in, whether a minimal severity criterion was employed, the number of centres involved, and the trial's total score on the CCDAN Quality Rating Scale (Moncrieff 2001).
4) Characteristics of participants, including gender distribution and mean and range of ages, mean length of time since diagnosis with PTSD, the number of participants in the sample with MDD, and the baseline severity of the PTSD symptom, as assessed on the CAPS, or the primary outcome measure for trials that do not employ the CAPS.
5) Outcome measures employed (primary and secondary), and summary continuous (means and standard deviations) and dichotomous (number of responders) data. Additional information will be included, such as whether data reflected the intent‐to‐treat (ITT) with last observation carried forward (LOCF) or completer/observed cases [OC] sample, and the minimal period required for inclusion of participants in the LOCF analyses. Other methods of estimating the outcome for participants who dropped out of the study, such as the mixed effects (ME) model, will also be recorded.
6) Quality assessment, including the number of randomised participants who were not included in the analysis (lost to follow‐up (LTF)), whether blinding occurred for the assessor/s and patients, as well as whether the allocation of TMS was randomised and the allocation sequence was concealed (the methods used in implementing these respective bias reduction measures will also be documented).
Assessment of methodological quality of included studies
The quality of the trials will be independently assessed by two authors using the CCDAN Quality Rating Scale (QRS) (Moncrieff 2001). This 23‐item scale assesses a range of features such as sample size, the duration of the intervention, inclusion and exclusion criteria, and whether or not the power of the trial to detect a treatment effect was calculated. In addition, data for other trial characteristics that have been recognised as potential sources of bias, such as the method used in generating the allocation sequence, the concealment of allocation, whether outcome assessment was blinded, and the number of participants lost to follow up, will be independently collated by two authors as part of the general data collection process (see Data extraction and management section). This is regarded as necessary given doubts concerning the usefulness of an overall quality score from a scale composed of multiple items (Alderson 2003).
Measures of treatment effect
Dichotomous data
Relative risk (RR) of response to treatment and number needed to treat to benefit (NNTB) will be calculated for the dichotomous outcome of interest (CGI‐I or related measure). Relative risk will be used instead of odds ratios, as odd ratios are less easily interpreted. Odds ratios also tend to overestimate the size of the treatment effect when interpreted as relative risks. This is especially the case when the occurrence of the outcome of interest is common (as anticipated in this review, with an expected response greater than 20%) (Deeks 2005). NNTB is defined as the inverse of the absolute risk difference due to the active intervention. In this review it will be used to indicate the number of patients who require treatment with rTMS, relative to a control, before a single additional patient in the rTMS group responds to treatment.
Continuous data
Weighted mean differences (WMD) will be calculated for continuous summary data derived from the same scale. In cases where a range of scales are employed for each outcome, such as in the assessment of comorbid depression on the MADRS and HAM‐D, the standardised mean difference (SMD) will be determined. This method of analysis standardises the differences between the means of the treatment and control groups in terms of the variability observed in the trial.
Studies with multiple treatment groups
In placebo‐controlled trials comparing the efficacy of different stimulation parameters in treating PTSD, the bias introduced through comparing the summary statistics for multiple groups against the same placebo control will be avoided by pooling the means and standard deviations across all of the treatment arms as a function of the number of participants in each arm.
Cross‐over trials
Cross‐over trials will only be included in the calculation of the outcomes of interest when it is (a) possible to extract outcome data from the first treatment period, or (b) when the inclusion of data from both treatment periods is justified through a wash‐out period of sufficient duration as to minimise the risk of carry‐over effects. The minimum wash‐out period required will be defined as the length of the period during which rTMS was administered. For trials that the washout period is regarded as adequate, data from both periods will only be included when it is possible to determine the standard error of the mean difference in response between groups (Elbourne 2002). The summary statistics required to derive the standard error of interest will be obtained from the trial report, or for trials for which this information is missing, will be imputed through averaging the relevant statistic from other included crossover trials with comparable control conditions.
Dealing with missing data
All analyses of dichotomous data will be intention‐to‐treat (ITT). The total number of participants randomised to the different comparison groups will be used as the denominator in comparisons of treatment response. Only data from trials that provide information on the original group size (prior to drop‐outs) will be included in the analyses of treatment response. Preference will be given to the inclusion of summary statistics for continuous outcome measures derived from mixed effects models, followed by last observation carried forward (LOCF) and observed cases (OC) summary statistics (in that order). This is in line with evidence that ME methods are more robust to bias than LOCF analyses (Verbeke 2000).
Assessment of heterogeneity
Heterogeneity of treatment response and symptom severity will be assessed visually from the forest plot of relative risk. This will help determine whether the differences between the results of trials were greater than would be expected by chance alone. Heterogeneity will also be assessed by means of the chi‐square test of heterogeneity. If the chi‐square test has a p‐value of less than 0.10, this will be interpreted as evidence of heterogeneity, given the low power of the chi‐square statistic when the number of trials is small (Deeks 2005).
In addition, the I‐square heterogeneity statistic reported by RevMan will be used to quantify the inconsistency of the trial results within each subgroup analysis (Higgins 2003). Differences on continuous measures in medication efficacy between these subgroups will be assessed by means of Deeks' stratified test of heterogeneity (Deeks 2001). This method subtracts the sum of the chi‐square statistics available for each of the subgroups in the study from the chi‐statistic available for all the trials, to provide a measure (Qb) of heterogeneity between groups. Differences in treatment response on the CGI‐I will be determined by whether the confidence intervals for the effect sizes of the subgroups overlap. This method was chosen in preference to the stratified test, due to inaccuracies in the calculation in RevMan of the chi‐square statistic for dichotomous measures (Deeks 2005).
Assessment of reporting bias
Publication is not necessarily related to study quality and indeed publication may imply certain biases (Dickersin 1992; Song 2000). Small‐sample effects (including publication bias) will be determined by visual inspection of a funnel plot of treatment response.
Data synthesis
Categorical and continuous treatment effects will be obtained from a random effects model (the random effects model includes both within‐study sampling error and between‐studies variation in determining the precision of the confidence interval around the overall effect size, whereas the fixed effects model takes only within‐study variation into account). The outcomes will be expressed in terms of an average effect size for each subgroup, as well as by means of 95% confidence intervals.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses will be undertaken (number of trials permitting) in order to assess the degree to which the size of the treatment effect on the primary outcome measure is systematically influenced by methodological and clinical differences between trials.
The trials will be grouped according to the following methodological sources of heterogeneity:
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The duration of the trial. Trials will be grouped according to whether they were conducted over a period of two weeks or less, on the basis of the finding that most sham‐controlled rTMS studies of treatment for depression take place over a two‐week period (Loo 2005).
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The length of follow‐up. The long term effects of treatment with TMS will be assessed by comparing outcome data collected immediately after the last treatment session with treatment response over a longer time span. This is important given the finding in a Cochrane review of TMS for depression of an effect of stimulation of the left DLPFC on outcome immediately after treatment but not after a period of two weeks (Martin 2003).
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The frequency of the stimulation used. Trials will be grouped according to whether they employed high (>1 Hz) or low (<1 Hz) frequency stimulation, given the different cortical effects associated with changes on this parameter.
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The site of stimulation. Studies will be stratified into three groups, based on the part of the brain targeted: (1) left prefrontal cortex (2) right prefrontal cortex, and (3) other brain areas.
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The intensity of stimulation. Trials will be classified as high intensity (defined as stimulation using a magnetic pulse of equal or greater intensity than the motor threshold) and low intensity (less than the motor threshold). Motor threshold is conventionally characterised on a per patient basis as the minimum strength of the magnetic pulse required to elicit a physiological response in at least half the trials when applied to the motor cortex. The responses of interest are most often the presence of a motor evoked potential in a hand muscle, or thumb movement in the contralateral hand.
In addition, the following criteria will be used to assess the influence of clinical sources of heterogeneity on treatment outcome (number of trials permitting):
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"Whether or not the sample included patients diagnosed with major depression. Such an analysis might assist in determining the extent to which the efficacy of TMS in treating PTSD is independent of its ability to reduce symptoms of depression.
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The age of participants. Trials of children and adolescents (<= 18 years) will be analysed separately from adults. In addition, trials of participants 55 years of age and above will only be included with the other adults trials should no heterogeneity between these groups be detected. This was regarded as necessary by the reviewers, due to evidence that older patients with MDD do not appear to respond to treatment with TMS (Nahas 2004).
Subgroup analyses will be undertaken (number of trials permitting) in order to assess the degree that clinical differences between trials might have systematically influenced differences observed in the primary treatment outcomes.
