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Clinical case
Patient
A 27-year-old woman.
Present illness
A 27-year-old female patient with chronic post-traumatic stress disorder (PTSD) and recurrent major depressive sisorder (MDD) is referred for consultation regarding possible repetitive transcranial magnetic stimulation (rTMS) treatment for her medication-resistant depression. She has no other medical diagnoses and had no history of substance abuse.
Present status
At the time of initial consult, psychometrics indicated that both PTSD symptoms and MDD symptoms were severe. While the patient passively endorses suicidal thoughts, she denies active intent or plan to harm herself. She has taken medical leave of absence from her job in order to get treatment for her depression. To review how rTMS may affect their patient’s PTSD symptoms, the consulting team conducts a review of published literature.
Background
PTSD is a severe psychiatric illness characterised by four core symptom clusters: re-experiencing, avoidance, negative cognition and mood and hyperarousal.1 With an estimated lifetime prevalence in community samples of up to 8%, PTSD results in a great deal of personal suffering and escalating social and economic costs.2 Unfortunately, current evidence-based treatments for PTSD leave a high percentage with a significant symptom burden, highlighting the urgent need for novel treatments. The growing acceptance3 of rTMS to the dorsolateral prefrontal cortex (DLPFC) for treatment-resistant MDD has evoked the question of its potential efficacy for PTSD.
Formulate your clinical question
What effect does excitatory rTMS over the left DLPFC have on symptoms of PTSD in patients undergoing rTMS treatments for depression?
Patients: patients with PTSD undergoing rTMS.
Intervention: accelerated protocol of rTMS to augment usual care (psychotropic medications±talk therapy).
Comparison: sham rTMS or usual care.
Outcomes: level of PTSD symptoms after treatment.
Literature search
PubMed, Ovid/Medline, and PsycInfo databases are queried with search terms ‘rTMS’, ‘transcranial magnetic stimulation’, ‘PTSD’ and ‘post-traumatic stress disorder.’ In a 2017 systematic review and meta-analysis4 by Yan and colleagues, pooled data from 13 original studies suggest that patients suffering from PTSD with or without a comorbid depressive disorder who received active rTMS experienced significant improvement in total PTSD scores and depression scores when compared with those who received sham treatment or usual treatment (medications only). These results were seen with both low frequency (LF, defined as <5 Hz) and high frequency (HF, defined as >5 Hz) stimulations administered to either the left or the right DLPFC. Importantly, here, there were no reports of worsened anxiety or PTSD-specific symptoms with active rTMS treatment.
Critical appraisal of a systematic review
First Judgement: Evaluate the credibility of the methods of systematic review
Did the review explicitly address a sensible clinical question?
Yes. The clinical question of this review may be summarised as follows:
P: patients with post-traumatic stress disorder (PTSD) with and without comorbid depression.
I: repetitive transcranial magnetic stimulation (rTMS) aiming to reduce PTSD symptoms.
C: sham transcranial m agnetic s timulation (TMS) or usual care.
O: level of PTSD symptoms after treatment.
Was the search for relevant studies exhaustive?
Yes. The review authors queried nine electronic databases (English databases: PubMed, The Cochrane Library, EMBASE, PsycInfo and ISI Web of Knowledge; Chinese databases: the Chinese Biomedical Literature Database, the Chinese National Knowledge Infrastructure, Weipu and WanFang). The search terms included medical subject headings, text keywords and their combinations (such as ‘transcranial magnetic stimulation’, ‘TMS’, ‘posttraumatic stress disorder’, ‘posttraumatic’, ‘post traumatic’ or ‘stress’). A total of 541 articles were found and 18 studies were included in the analysis and review. Of these, data from 13 studies were included in the meta-analysis. The search terms in the appendix looks comprehensive.
Were selection and assessments of studies reproducible?
Yes. Two of the paper’s five authors were responsible for selection of included studies and extraction of data. While the review authors do not comment on the inter-rater agreement of these, they did provide detailed description of the inclusion criteria and quality appraisal criteria used, as well as their method for resolving differences between evaluations of the two reviewers.
Did the review present results that are ready for clinical application?
YES and NO. The authors could not calculate the number needed to treat, since only three of the 13 included studies reported treatment response rate, and none of the studies reported the remission rate. Thus, absolute risk reduction for clinical practice is unknown. Moreover, none of the included studies have been replicated due to heterogeneity of recruitment samples (patients with and without comorbid depression) stimulation paradigms (different types of treatment coils and sham control and a wide range of total stimulus pulses per day), study design (blinded vs open label) and outcome measures, while the meta-analysis found that the treatment effect of active rTMS remained significant after accounting for the degree of heterogeneity; nevertheless, the results should be interpreted with caution.
Did the review address confidence in estimates of effect?
Yes. The review authors provided enough information for readers to judge confidence in study results.
Second Judgement: Rate the confidence in the effect estimates
How serious is the risk of bias in the body of evidence?
Moderately serious. The risk of reporter bias is high since the meta-analysis included data from open-label trials; moreover, all of the included studies based their conclusions of treatment effect on symptom questionnaires, the results of which can be easily influenced by expectations. While the randomised controlled trials (RCTs) included a sham condition, the authors do not comment on the efficacy of the blinding of participants and personnel. Finally, only two of the RCTs included raw data for analysis of variance of repeated measures to compare score changes.
How precise are the results?
This study’s results are fairly imprecise. In general, the active treatment condition in each of the 13 original studies produced a fairly consistent improvement in total PTSD scores and depression scores when compared with those who received sham treatment or usual treatment. However, the degree of improvement relative to intervention is unclear due to heterogeneity and intrinsic limitations of outcome measures used in the original studies.
Are the results consistent across studies?
No. As mentioned above, included studies reported outcomes using differing outcome measures. The authors performed the I2 test to account for the heterogeneity and guide their use of fixed-effect or random-effect regression models in their interpretation of the data. They reported on effect size using standard mean difference.
Do the results directly apply to my patient?
No. While the review included patients with comorbid major depressive disorder and PTSD, none of the studies included patients who were currently experiencing a severe episode of depression during the time they were enrolled in the study. At the time she initiated treatment, our patient was experiencing severe depression and moderate PTSD symptoms, and her left-sided treatment was primarily purposed to treat depressive symptoms. In addition, these studies implemented a standard3 treatment protocol rather than the accelerated protocol used in the case presented. While accelerated treatment paradigms (including those with six treatments delivered daily) have been safely delivered5 to depressed patients without any clear adverse effects, it is unknown what effect the acceleration of treatment may have had on the patient’s PTSD symptoms.
Is there concern about reporting bias?
No. The number of included studies (13 out of 18 relevant trials) is too small to statistically examine the possibility of publication bias. The literature search appeared fairly comprehensive.
What will you do with your patient?
The consulting team recommends that the patient proceeds with rTMS treatment. Prior to treatment, resting motor threshold (rMT) is determined (37 mV) and treatment site is located. The patient receives an accelerated course of rTMS with the following parameters: 18 Hz, 2 s on, 12 s wait time, 55 trains at 120% rMT x two sessions, total 1980 pulses each session, averaging four sessions per day and 5 days per week for 4 weeks with a Brainsway H-Coil over left DLPFC. During the rTMS course, the patient continues her outpatient regimen of Venlafaxine ER 300 mg daily, Bupropion XL 450 mg daily, Prazosin 7 mg at bedtime in addition to weekly psychotherapy. She tolerates the treatments without difficulty, with notable improvement in her mood within the first 14 days of treatment. However, as treatments continue and the patient nears euthymia, she begins to experience a paradoxical worsening in her PTSD re-experiencing symptoms (flashbacks, dissociation and intrusive memories), to the point that her suicidal ideation returns. Treatments are discontinued and the re-experiencing symptoms begin to improve within 48 hours. At a 3-week post-treatment follow-up, suicidal thoughts have resolved and core PTSD symptoms have improved across all domains—a delayed response that persists through 4-month follow-up.
Discussion
In the case presented, left-sided excitatory (18 Hz) stimulation over the DLPFC improved mood symptoms but transiently worsened PTSD symptoms. It is impossible to ascertain whether this symptom exacerbation was due primarily to rTMS treatments or whether confounding environmental factors (time away from work, contact with triggering environmental stimuli, psychodynamics of intensive daily treatments and so on) might have affected treatment response. Once rTMS treatments concluded, long-term potentiation of rTMS-related brain changes may have produced the gradual but dramatic improvement in PTSD core symptoms beyond the pre-rTMS level. This case highlights the need for a better understanding of the short-term and long-term effects of rTMS for PTSD. Future work on the subject should strive to eliminate confounding variables, add a sham condition and recruit for larger sample sizes.
Footnotes
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.