Repetitive transcranial magnetic stimulation for post-traumatic stress disorder in adults

The estimated lifetime prevalence of post-traumatic stress disorder (PTSD) in adults worldwide has been estimated at 3.9%. PTSD appears to contribute to alterations in neuronal network connectivity patterns. Current pharmacological and psychotherapeutic treatments for PTSD are associated with inadequate symptom improvement and high dropout rates. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive therapy involving induction of electrical currents in cortical brain tissue, may be an important treatment option for PTSD to improve remission rates and for people who cannot tolerate existing treatments.

To assess the effects of repetitive transcranial magnetic stimulation (rTMS) on post-traumatic stress disorder (PTSD) in adults.

We searched the Cochrane Common Mental Disorders Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two clinical trials registers. We checked reference lists of relevant articles. The most recent search was January 2023.

We included randomized controlled trials (RCTs) assessing the efficacy and safety of rTMS versus sham rTMS for PTSD in adults from any treatment setting, including veterans. Eligible trials employed at least five rTMS treatment sessions with both active and sham conditions. We included trials with combination interventions, where a pharmacological agent or psychotherapy was combined with rTMS for both intervention and control groups. We included studies meeting the above criteria regardless of whether they reported any of our outcomes of interest.

Two review authors independently extracted data and assessed the risk of bias in accordance with Cochrane standards. Primary outcomes were PTSD severity immediately after treatment and serious adverse events during active treatment. Secondary outcomes were PTSD remission, PTSD response, PTSD severity at two follow-up time points after treatment, dropouts, and depression and anxiety severity immediately after treatment.

We included 13 RCTs in the review (12 published; 1 unpublished dissertation), with 577 participants. Eight studies included stand-alone rTMS treatment, four combined rTMS with an evidence-based psychotherapeutic treatment, and one investigated rTMS as an adjunctive to treatment-as-usual. Five studies were conducted in the USA, and some predominantly included white, male veterans. Active rTMS probably makes little to no difference to PTSD severity immediately following treatment (standardized mean difference (SMD) -0.14, 95% confidence interval (CI) -0.54 to 0.27; 3 studies, 99 participants; moderate-certainty evidence). We downgraded the certainty of evidence by one level for imprecision (sample size insufficient to detect a difference of medium effect size). We deemed one study as having a low risk of bias and the remaining two as having 'some concerns' for risk of bias. A sensitivity analysis of change-from-baseline scores enabled inclusion of a greater number of studies (6 studies, 252 participants). This analysis yielded a similar outcome to our main analysis but also indicated significant heterogeneity in efficacy across studies, including two studies with a high risk of bias. Reported rates of serious adverse events were low, with seven reported (active rTMS: 6; sham rTMS: 1). The evidence is very uncertain about the effect of active rTMS on serious adverse events (odds ratio (OR) 5.26, 95% CI 0.26 to 107.81; 5 studies, 251 participants; very low-certainty evidence [Active rTMS: 23/1000, sham rTMS: 4/1000]). We downgraded the evidence by one level for risk of bias and two levels for imprecision. We rated four of five studies as having a high risk of bias, and the fifth as 'some concerns' for bias. We were unable to assess PTSD remission immediately after treatment as none of the included studies reported this outcome.

Based on moderate-certainty evidence, our review suggests that active rTMS probably makes little to no difference to PTSD severity immediately following treatment compared to sham stimulation. However, significant heterogeneity in efficacy was detected when we included a larger number of studies in sensitivity analysis. We observed considerable variety in participant and protocol characteristics across studies included in this review. For example, studies tended to be weighted towards inclusion of either male veterans or female civilians. Studies varied greatly in terms of the proportion of the sample with comorbid depression. Study protocols differed in treatment design and stimulation parameters (e.g. session number/duration, treatment course length, stimulation intensity/frequency, location of stimulation). These differences may affect efficacy, particularly when considering interactions with participant factors. Reported rates of serious adverse events were very low (< 1%) across active and sham conditions. It is uncertain whether rTMS increases the risk of serious adverse event occurrence, as our certainty of evidence was very low. Studies frequently lacked clear definitions for serious adverse events, as well as detail on tracking/assessment of data and information on the safety population. Increased reporting on these elements would likely aid the advancement of both research and clinical recommendations of rTMS for PTSD. Currently, there is insufficient evidence to meta-analyze PTSD remission, PTSD treatment response, and PTSD severity at different periods post-treatment. Further research into these outcomes could inform the clinical use of rTMS. Additionally, the relatively large contribution of data from trials that focused on white male veterans may limit the generalizability of our conclusions. This could be addressed by prioritizing recruitment of more diverse participant samples.