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. Author manuscript; available in PMC: 2019 Aug 1.
Published in final edited form as: J Affect Disord. 2018 Apr 5;235:414–420. doi: 10.1016/j.jad.2018.04.009

5 Hz Repetitive Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder Comorbid with Major Depressive Disorder

Linda L Carpenter a,*, Christine Conelea c,b, Audrey R Tyrka a, Emma S Welch a, Benjamin D Greenberg a,b, Lawrence H Price a, Matthew Niedzwiecki a, Agustin G Yip a, Jennifer Barnes a, Noah S Philip a,b
PMCID: PMC6567988  NIHMSID: NIHMS1034053  PMID: 29677606

Abstract

Background:

Standard clinical protocols for repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) apply 10 Hz pulses over left prefrontal cortex, yet little is known about the effects of rTMS in more diagnostically complex depressed patients.

Objective/Hypothesis:

Posttraumatic stress disorder (PTSD) is commonly comorbid with MDD, and while rTMS has been shown to alleviate PTSD symptoms in preliminary studies, ideal parameters remain unclear. We conducted a prospective, open-label study of 5 Hz rTMS for patients with comorbid PTSD+MDD and hypothesized stimulation would reduce symptoms of both disorders.

Methods:

Outpatients (N=40) with PTSD+MDD and at least moderate global severity were enrolled. 5 Hz rTMS included up to 40 daily sessions followed by a 5-session taper. Symptoms were measured using the PTSD Checklist (PCL-5) and Inventory of Depressive Symptomatology, Self-Report (IDS-SR). Baseline-to-endpoint changes were analyzed.

Results:

The intent-to-treat population included 35 participants. Stimulation significantly reduced PTSD symptoms (PCL-5 baseline mean±SD score 52.2±13.1 versus endpoint 34.0±21.6; p<.001); 23 patients (48.6%) met a pre-defined categorical PTSD response criteria. MDD symptoms also improved significantly (IDS-SR, baseline 47.8±11.9 to endpoint 30.9±18.9; p<.001); 15 patients (42.9%) demonstrated categorical response and 12 (34.3%) remitted. PTSD and MDD symptom change was highly correlated (r=.91, p<.001).

Limitations:

Unblinded single-arm study, with modest sample size.

Conclusion:

Significant and clinically meaningful reductions in both MDD and PTSD symptoms were observed following stimulation. The preliminary efficacy of 5 Hz rTMS for both symptom domains in patients with comorbid disorders supports future controlled studies.

(5 Hz Repetitive Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder Comorbid With Major Depressive Disorder; Clinicaltrials.gov; NCT02273063)

Keywords: repetitive transcranial magnetic stimulation, posttraumatic stress disorder, major depressive disorder, 5 Hz

INTRODUCTION

Repetitive transcranial magnetic stimulation (rTMS) therapy has emerged as an important standard-of-care treatment for adults with major depressive disorder (MDD) that do not benefit from standard antidepressant treatments. Due to concerns about comorbid psychiatric conditions introducing disease heterogeneity into study samples (O’Reardon et al., 2007; George et al., 2010; Levkovitz et al., 2015) regulatory MDD rTMS trials systematically excluded adults who were concurrently experiencing threshold symptoms of comorbid anxiety, obsessive-compulsive and/or posttraumatic stress disorder (PTSD). In real-life practice, however, clinicians are faced with the challenge of treating patients who are more diagnostically complex than those who meet stringent research clinical trial eligibility criteria.

PTSD is a common psychiatric disorder that can result in significant symptoms and psychosocial dysfunction. It is estimated that approximately 7% of the U.S. population experiences PTSD over the course of their lifetime (Kessler et al., 2005), and 50–70% of Veterans are diagnosed with PTSD (Hoge et al., 2004). Exposure to severe traumatic events is common among civilians living in urban areas, and PTSD occurs in one third of those exposed (Alim et al., 2008). PTSD is associated with diminished physical health and unemployment (Thomas et al., 2010), making it an important public health problem. Furthermore, PTSD and MDD are highly comorbid; up to 50% of patients with PTSD are also diagnosed with MDD (Rytwinkski et al., 2013; Flory and Yehuda, 2015). In both disorders, a substantial number of patients remain symptomatic despite standard treatments (Trivedi et al., 2006; Rush et al., 2006; Watts et al., 2013). Patients with comorbid MDD and PTSD symptoms have poorer treatment outcomes for both pharmacotherapy and psychotherapy (Holtzheimer et al., 2005; Campbell et al., 2007) and as such are well represented among those with treatment-resistant major depression referred for rTMS therapy.

A handful of small pilot studies (see review (Karsen et al., 2014)) suggest rTMS therapy holds potential for improving PTSD symptoms. However, while rTMS has been developed as an effective treatment for depression over the past decade, less attention has been focused on determining its use for PTSD. Optimal rTMS stimulation parameters have not been identified for treatment when PTSD is a comorbid disorder. Boggio et al. (2010) found that 10 sessions of rTMS delivered to PTSD patients (N = 30) at a relatively high frequency (20 Hz) on either the left or right prefrontal cortex (PFC) was associated with significant clinical improvement compared to sham. Left-sided stimulation appeared to specifically benefit mood symptoms, whereas right-sided treatment was associated with greater improvement in anxiety symptoms. Watts et al. (2012) reported significant and persistent improvement in PTSD symptoms alongside significant mood benefits following delivery of 10 rTMS sessions to the right PFC at a low frequency (1 Hz) in a PTSD sample (n=20).

Successful use of both higher (20 Hz) and lower (1 Hz) pulse frequencies in these pilot studies suggest that magnetic fields delivered in a broad range of pulse frequencies induce physiologic effects on neuronal function. For MDD, a compelling evidence base exists for 10 Hz rTMS (over left PFC) using a figure-8 coil, or 18 Hz stimulation (over left>right bilateral PFC) with an H-coil (McClintock et al., 2017). A growing body of work has also demonstrated that 1 Hz rTMS to PFC on the right side produces significant antidepressant effects (Berlim et al., 2013), as well as prominent anxiolytic effects in patients with anxious depression (Rossini et al., 2010).

Owing to the sheer number of stimulation parameters contributing to the overall “dose” of rTMS and the need to manipulate only one in each clinical trial, relatively little has been done to systematically test efficacy of stimulation between 1 and 10 Hz. Several studies have employed a stimulation frequency of 5 Hz (left PFC) and reported outcomes equivalent to those achieved with 10 Hz for treating depression in bipolar patients (George et al., 2000; Nahas et al., 2003; Rumi et al., 2005; Su, et al., 2005; Avery, et al., 2008). Fitzgerald et al. (2009) randomized MDD patients (nonresponders to right-sided 1 Hz rTMS) to receive either 5 Hz or 10 Hz stimulation on the left side, and found equivalent antidepressant efficacy. 5 Hz stimulation using an H-coil produced significant improvement in social anxiety and social relatedness when compared with sham in an autism sample (Enticott et al., 2014). An open-label study in patients with comorbid MDD+PTSD (Rosenberg et al., 2002) demonstrated modest improvements in both mood and PTSD symptoms when 1 Hz and 5 Hz stimulation were delivered over left PFC, but the rTMS treatment protocol included only 600 pulses/day and a total of only 10 sessions, which would be considered a very low or inadequate “dose” of rTMS by current standards.

Our group has systematically administered 5 Hz rTMS therapy to MDD patients in our clinics to address high levels of comorbid anxiety or activation emerging during standard 10 Hz therapy, which can be particularly problematic when rTMS is given as an adjunct to ongoing monoaminergic antidepressants or other stimulating medications (Philip et al., 2015). MDD efficacy outcomes for patients receiving 5 Hz rTMS (to left PFC) were equivalent to those getting 10 Hz, and the slower pulse frequency was better tolerated. We also examined acceptability and safety of 5 Hz rTMS in a case series (n=10) and reported reductions in PTSD and MDD symptoms, along with excellent tolerability (Philip et al., 2016).

This literature and our prior experience laid the groundwork for a prospective open-label study of rTMS delivered at 5 Hz over the left (dorsolateral) PFC in patients with comorbid PTSD and MDD, designed to both characterize efficacy and safety of the protocol. We hypothesized that 5 Hz stimulation over left PFC would significantly reduce both PTSD and MDD symptoms with a safety and tolerability profile comparable to prior rTMS studies.

METHODS

Study overview

This study was a prospective, open-label trial of rTMS delivered to outpatients who were symptomatic despite ongoing naturalistic pharmacotherapy for PTSD and MDD. The study occurred at two collaborating sites associated with the Alpert Medical School of Brown University: Butler Hospital (BH) and the Providence Veteran’s Administration Medical Center (PVAMC). The institutional review boards (IRBs) at both sites approved the study, and all participants provided written informed consent for participation in the trial (ClinicalTrials.gov NCT02273063).

Eligibility was determined during an in-person screening visit. Eligible participants returned within two weeks to complete baseline assessments and begin rTMS. The rTMS treatment course allowed up to 40 sessions, delivered once per day, with the first 35 delivered on weekdays over 7 weeks and the final 5 on a taper schedule over 3 weeks. The maximum of 40 treatments for this acute series was informed by prior research suggesting that longer acute phase may be associated with superior clinical outcomes (Avery et al., 2008). Patients who achieved remission (operationally defined as 2 consecutive weeks of scores consistent with remission using measures described below) prior to treatment 35 could be tapered.

Participants

Participants were adults aged 18–75 years who met DSM-IV criteria for both PTSD (acute or chronic) and MDD (nonpsychotic, recurrent, or chronic) at the time of the screening and baseline visits. Clinicians with experience treating both disorders (NSP, LLC) verified the diagnoses. Either diagnosis could be considered “primary,” but both disorders must have separately met an overall illness severity rating of at least “moderately ill” on the Clinical Global Impressions-Severity Scale (CGI-S (Guy, 1976)). Participants lacked response to, or demonstrated intolerance to, at least one antidepressant medication trial as part of definitive and adequate treatment in the current depressive episode; were on stable psychotropic regimens for at least six weeks prior to enrollment; could independently read and understand study measures/instructions; and females with child bearing potential agreed to use acceptable birth control methods. Stable, ongoing psychotherapy was permitted during the study. These participants were unique from our prior reports of 5Hz rTMS for depression (Philip et al., 2015) and PTSD (Philip et al., 2016).

Candidates were excluded for: past rTMS treatment; breastfeeding, pregnancy or plans to become pregnant within the next three months; lifetime history of significant head injury (i.e., resulting in loss of consciousness greater than 10 minutes or documented evidence of brain injury); current/past significant neurological disorder (e.g., seizure disorder, brain tumors, stroke, cerebral aneurysm); current psychotic, bipolar I, alcohol and/or substance dependence or abuse disorders; active suicidal intent or plan, or any other contraindication to study procedures.

Assessments

Primary outcomes for this study were change in PTSD and MDD symptom severity from baseline to post-treatment. The PTSD Checklist for DSM-5 (PCL-5 (Weathers et al., 2013) was used to measure PTSD symptoms, and MDD severity was measured using the Inventory of Depressive Symptomology-Self Report (IDS-SR (Rush et al., 1996)). Both scales were administered at baseline, biweekly during the first 4 weeks, weekly during the remainder of treatment, and within 72 hours after the final treatment session. Scores on the PCL-5 were examined for clinically meaningful improvement (≥10 point reduction from baseline, per Weathers et al. (2013)) and categorical response (operationally defined as a score of ≤33 at post-treatment together with clinically meaningful improvement). Clinical response on the IDS-SR was defined as a ≥50% reduction from baseline score, and remission as IDS-SR score of ≤14 at post-treatment.

Secondary outcome measures administered at baseline and post-treatment assessed change in overall clinical state as determined by clinician and patient ratings of global illness severity (CGI-S and the equivalent patient self-rated version, PGI-S) and baseline-to-endpoint global improvement (CGI-I and PGI-I). Additional measures of pre- and post-TMS symptom severity included the Patient Health Questionnaire (PHQ-9 (Kroenke et al., 2001)), the 42-item Depression Anxiety Stress Scale (DASS (Lovibond and Lovibond, 1995)), and the Perceived Stress Scale (PSS (Cohen et al., 1983)).

Baseline measures of childhood/adolescent exposure to abuse and neglect were assessed with the 28-item Childhood Trauma Questionnaire (CTQ (Bernstein et al., 2003)). Additional lifetime traumatic event detail was captured with the Life Events Checklist (LEC (Weathers et al., 2013)). LEC items endorsed as “happened to me” or “witnessed” were counted.

Treatment-emergent side effects, captured by spontaneous report and in response to specific daily queries made by TMS staff during the course of treatment, were categorized as serious or nonserious, and any interventions taken to address emergent adverse effects were recorded.

TMS device and treatment parameters

Prior to the first treatment session, the motor threshold (MT) was obtained in order to determine treatment intensity using the NeuroStar TMS Therapy System (Neuronetics, Inc., Malvern, PA). The same device was used for subsequent rTMS treatments delivered over the left PFC, determined by the standard F3 location using the international EEG 10/20 system measurements. Stimulation parameters were as follows: frequency = 5 Hz, 5 sec stimulation train, 14 sec inter-train interval, 3000 pulses per session, intensity 120% MT. Per standard clinical practice, total pulses per session was increased to 4000 (with the inter-train interval shortened by 1 sec) for the remainder of the treatment course when participants did not have at least 30% improvement from baseline scores at treatment 15.

Statistical Analyses

Data were analyzed in an intent-to-treat (ITT) fashion, such that any participant who signed informed consent and received at least one rTMS session were included in the ITT sample, using the last observation carried forward (LOCF) method. Descriptive statistics were used to examine baseline sample characteristics. Paired sample-t tests characterized outcomes post-treatment on continuous measures (PCL-5, IDS-SR, PHQ-9, DASS, PSS, CGI-S, PGI-S). Effect sizes were calculated for primary outcome measures PCL-5 and IDS-SR using Cohen’s dav (Lakens, 2013). Pearson correlations evaluated the relationship between PTSD and MDD symptom change following rTMS. We also examined potential variables of interest as predictors of clinical response, including depressive and PTSD symptom severity (total and subscale values), and baseline values of stress and anxiety on the DSS. Analyses were conducted in SPSS version 22 (IBM, Armonk, NY).

RESULTS

Demographic and clinical characteristics

Forty participants signed informed consent, and 35 comprised the ITT population. Reasons for dropout prior to starting rTMS included failure to meet eligibility criteria upon screening (n=2) and withdrawal of consent/changed mind (n=3). Demographic and clinical characteristics (n=35) are presented in Table 1. The mean±SD age was 51.6±10.3. Sixty percent had a past history of inpatient psychiatric hospitalization, and 48.6% had prior intensive outpatient or partial hospitalization. Reflecting the significant disability associated with comorbid PTSD and MDD, 68.5% (n=24) were either unemployed or on disability. Trauma exposure included a broad range of LEC trauma types and 82.9% of participants reported a history of at least “moderate” childhood maltreatment on one or more CTQ subscales. No patients with Bipolar II were enrolled in the study.

Table 1.

Baseline demographic and clinical characteristics

Characteristics N = 35
Study site, n (%) BH: 18 (51.4%)
VA: 17 (48.6%)
Age, mean (SD, range) 51.6 (10.3, 27–69)
Sex, n (%) Male: 21 (60.0%)
Female: 14 (40.0%)
Race, n (%) White: 33 (94.3%)
Black: 1 (2.9%)
More than one race: 1 (2.9%)
Highest level of education, n (%) Less than high school: 1 (2.9%)
High school or equivalent: 7 (20.0%)
Vocational degree or some college: 15 (42.9%)
College or advanced degree: 12 (34.2%)
Employment status, n (%) Full time: 5 (14.3%)
Unemployed: 3 (8.6%)
Disability: 21 (60.0%)
Retired: 6 (17.1%)
Prior ECT 1 (2.9%)
History of psychiatric hospitalization 21 (60.0%)
History of psych partial hospitalization 17 (48.6%)
Childhood Trauma Questionnaire (CTQ)*
 Total score, mean (SD) 71.6 (18.5)
 CTQ Categories, n (% meeting subscale score for at least “moderate” degree of trauma)
 Emotional abuse 21 (60%)
 Physical abuse 14 (40%)
 Sexual abuse 26 (74.3%)
 Emotional neglect 19 (54.2%)
 Physical neglect 20 (57.1%)
 Any subtype of maltreatment, n (%) 29 (82.9%)
Life Events Checklist (LEC)**
 Natural disaster, n (%) 7 (20.0%)
 Fire or explosion, n (%) 7 (20.0%)
 Transportation accident, n (%) 13 (37.1%)
 Serious accident, n (%) 10 (28.6%)
 Exposure to toxic substance, n (%) 2 (5.7%)
 Physical assault, n (%) 17 (48.6%)
 Assault with a weapon, n (%) 9 (25.7%)
 Sexual assault, n (%) 14 (40.0%)
 Other unwanted sexual experience, n (%) 17 (48.6%)
 Combat or war-zone exposure, n (%) 8 (22.9%)
 Captivity, n (%) 1 (2.9%)
 Life-threatening illness/injury, n (%) 11 (31.4%)
 Severe human suffering, n (%) 11 (31.4%)
 Sudden violent death, n (%) 8 (22.9)
 Sudden accidental death, n (%) 7 (20.0)
 Caused serious harm, n (%) 4 (11.4)
 Other, n (%) 11 (31.4)
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*

CTQ not completed by one subject.

**

LEC items endorsed as “Happened to me” or “Witnessed”

Mean (±SD) number of treatment sessions was 32.9±9.3, range 5–40. Thirty (86%) patients completed final assessments after their last treatment session. The remaining five did not complete due to treatment-emergent adverse events or withdrawal of consent/lost to follow-up (see Safety Outcomes, below).

Clinical outcomes

Clinical outcomes are summarized in Table 2. Results show significant improvement in primary outcomes of both PTSD and MDD severity. PCL-5 scores significantly decreased from baseline (mean±SD, 52.2±13.1) to post-treatment (34.0±21.6; t = 5.6, p<.001), with a mean 35.5% change (±38.0%; range −50.0 to 90.9%) and a large observed effect size (dav = 1.04). IDS-SR scores also significantly decreased from baseline (47.8±11.9) to post-treatment (30.9±18.9; t = 6.6, p<.001). Mean IDS-SR percent change was 37.6% (±32.3%, range −26.5 to 86.0%), and the effect size was large (dav = 1.09). There was a trend-level site difference in percent change on IDS-SR (p<.10), but outcomes were equivalent across sites on other measures. Percent change scores on the IDS-SR and PCL-5 were highly correlated (r = .92, p<.001).

Table 2.

Outcome measures

Measure Baseline Post-treatment t p
Primary outcome measures
IDS-SR total score, mean (SD) 47.8 (11.9) 30.9 (18.9) 6.6 <.001
IDS-SR percent change, mean (SD), range 37.6% (32.3),
−26.5%−86.0%
PCL-5 total score, mean (SD) 52.2 (13.1) 34.0 (21.6) 5.6 <.001
PCL-5 percent change, mean (SD), range 35.5 (38.0),
−50.0%−90.9%
Secondary outcome measures
PHQ-9 total score, mean (SD) 18.4 (5.0) 10.7 (7.9) 7.3 <.001
DASS total score, mean (SD) 67.4 (26.7) 43.7 (32.5) 5.4 <.001
DASS Depression subscale total score, mean (SD) 27.6 (11.1) 18.6 (14.6) 4.2 <.001
DASS Anxiety subscale total score, mean (SD) 17.0 (9.5) 10.9 (9.5) 5.6 <.001
DASS Stress subscale total score, mean (SD) 22.8 (9.8) 14.1 (11.6) 5.2 <.001
PSS total score, mean (SD) 34.9 (6.6) 27.1 (10.2) 4.9 <.001
CGI-S score, mean (SD) 5.1 (0.6) 2.8 (1.7) 7.1 <.001
PGI-S score, mean (SD) 5.4 (0.7) 4.3 (1.2) 4.7 .001
CGI-I score, n (%) Very much improved: 12 (34.3%)
Much improved: 4 (11.4%)
Minimally improved: 4 (11.4%)
No change: 3 (8.6%)
Minimally worse: 1 (2.9%)
Much worse: 0
Categorical outcomes
IDS-SR Response, n (%) 15 (42.9)
IDS-SR Remission, n (%) 12 (34.3)
PCL-5 Response, n (%) 17 (48.6)
Met response criteria on both IDS-SR and PCL-5, n (%) 14 (40.0)
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Key: IDS-SR, Inventory of Depressive Symptomatology; SD, standard deviation; PCL-5, PTSD Checklist for DSM5; PHQ-9, Patient Health Questionnaire 9; DASS, Depression Anxiety Stress Scale; PSS, Perceived Stress Scale; CGI-S, Clinician-rated Clinical Global Impression of Severity; PGI-S, Patient-rated Clinical Global Impressions of Severity; CGI-I, Clinician-rated Clinical Global Impressions of Improvement.

Fifteen patients (42.9%) met the IDS-SR response criterion and 12 (34.3%) met remission criterion. Twenty-three patients (65.7%) experienced clinically meaningful improvement (PCL-5 reduction of ≥10 points), and 17 (48.6%) met operational criteria for response. Fourteen (40.0%) patients met response criteria on both MDD and PTSD measures.

Results also showed significant improvements on all secondary outcome measures (see Table 2). Clinician and patient ratings on the CGI-S/PGI-S scores were significantly better at study endpoint, and improvement ratings (CGI-I) indicated nearly half of patients were either “much improved” (11.4%) or “very much improved” (34.3%). One participant (2.9%) was rated “minimally worse.”

Post-hoc exploratory analyses were conducted to evaluate whether baseline severity of MDD or PTSD symptoms was related to “global response” status, defined as meeting response criteria for both IDS-SR and PCL; Table 3. A significant negative correlation was found between baseline depression severity and global response (rpb = −.38, p = .01), suggesting patients with more severe depression symptoms at baseline were less likely to have robust response in both diagnostic domains. Global response status was also negatively correlated with baseline PCL-5 Cluster C Avoidance score (rpb = −.42, p = .01), i.e., greater levels of PTSD-related avoidance were associated with lower likelihood of responding. Global response status was not significantly related to other measures of baseline PTSD severity or to baseline anxiety or stress ratings. All other predictors of response were nonsignificant (all p>.1).

Table 3.

Point biserial correlation coefficients between baseline clinical measures and meeting response status on both IDS-SR (depression) and PCL-5 (PTSD) scales

Baseline Measure rpb
IDS-SR total score -.38*
PCL-5 total score −.21
PCL-5 subscales
 Cluster B Re-Experiencing total score −.11
 Cluster C Avoidance total score −.42*
 Cluster D Negative Cognitions and Mood total score −.16
 Cluster E Arousal total score −.08
PSS total score −.31
DASS-Anxiety total score −.25
DASS-Stress total score −.15
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*

p < .05

Safety outcomes

Four (11.4%) patients experienced serious adverse events; three required hospitalization for worsening symptoms with suicidality, and one for suicidality and substance abuse. One experienced exacerbation of migraine and stopped after treatment #31 due to headaches and lack of clinical response. Fourteen (40%) experienced at least mild activation (defined as emergence or worsening of insomnia, irritability, anxiety, or agitation) during the course of TMS; all but one of these was taking stimulants or bupropion. Benzodiazepines were added to address activation in two cases, and dose reduction or discontinuation of a stimulating medication (bupropion or stimulants) was instituted in the others. Following this observation, Fisher’s Exact tests were used to explore the relationship between stimulant/bupropion use and activation, and we found a significant relationship between TMS-emergent activation and ongoing concurrent stimulant/bupropion-treatment (p<.001).

DISCUSSION

This is the first report describing potential efficacy of 5 Hz rTMS to target symptoms of comorbid PTSD and MDD. Notwithstanding limitations of an unblinded prospective trial design, our results indicate 5 Hz rTMS delivered to left dorsolateral PFC (as adjunct to ongoing ineffective pharmacotherapy) is generally safe and significantly reduces symptoms of both disorders. Symptom improvement in both MDD and PTSD domains was observed, and 40% of the sample met criteria for categorical response on both the MDD and PTSD severity scales. General safety of 5 Hz stimulation was confirmed, though several patients taking concurrent medications with stimulating effects on the central nervous system (CNS) required dose reduction or medication discontinuation so they could continue with the 5 days/week rTMS schedule.

The presence of a comorbid anxiety disorder was previously reported to predict inferior symptom outcomes in a large randomized trial of patients with primary MDD (Lisanby et al., 2009). The patients in our sample epitomized a cohort that would be excluded from regulatory trials by virtue of their active diagnostic and clinical comorbidity, reliance on complex pharmacotherapy regimens despite minimal substantive benefit, past treatment history (e.g., 60% previously treated on an inpatient basis), and history of significant early life trauma. Nevertheless, we observed large effect sizes with 5 Hz rTMS, comparable to other studies of rTMS for PTSD (Clark et al., 2015) and for pharmacoresistant MDD (O’Reardon et al., 2007). We observed a 43% antidepressant response rate and 34% depressive episode remission rate, both comparable to outcomes for primary MDD patients in an industry-sponsored prospective open-label MDD trial that used restrictive inclusion/exclusion criteria (Avery et al., 2008). While preliminary in nature, our results suggest that rTMS can be successfully used in patients with an otherwise poor prognosis and for whom the treatment may represent a desirable alternative option to electroconvulsive therapy.

There were no seizures and only one patient experienced headaches of sufficient intensity and duration to prompt early discontinuation after six weeks of daily sessions. Three of the 4 cases where suicidal ideation prompted transfer to inpatient care occurred near the end of the acute course or during the taper phase, as patients approached the maximum allowable number of treatments (following sessions #29, #36, and #37). Based on our clinical observations, increased hopelessness following weeks of daily treatments without substantial improvement contributed to decompensation at the end of the course for three nonresponders. Increased impulsivity or substance use characterized adverse events for two veterans. Without a sham comparison condition, it is difficult to know whether the events were specifically related to rTMS.

We also observed significant rates of TMS-associated activation with 5 Hz TMS. We are not able to compare these rates to similar studies using 10 Hz TMS (e.g., O’Reardon et al., 2007, George et al., 2010, Levkovitz et al., 2015) as those studies did not include patients with comorbid PTSD. As noted above, the vast majority of these participants were taking stimulants or related compounds, and further research is needed to prospectively characterize and evaluate the relationship between TMS-related activation, psychiatric comorbidity, and CNS-stimulating drugs.

While 5 Hz rTMS as an adjunct to ongoing pharmacotherapy regimens is generally well tolerated (Philip et al., 2015), we observed that patients in this study taking concurrent stimulant medications or highly noradrenergic agents were still vulnerable to experiencing excessive activation (emergence or worsening of insomnia, irritability, anxiety, or agitation) with daily treatments. rTMS-emergent signs of activation can be detected early with focused daily clinical assessment and are easily managed in the majority of cases, but dose reduction or discontinuation of nonessential agents with stimulating CNS effects prior to starting a course of TMS may represent the best strategy for clinical practice.

We found that 5 Hz rTMS to left PFC appeared to work well for reducing symptoms of both comorbid disorders rather than preferentially acting on either MDD or PTSD symptom domains. Our data revealed that baseline-to-endpoint change on PTSD and MDD scales were highly correlated throughout the study. These findings are consistent with our prior case-series observation that 5 Hz rTMS was helpful in PTSD (Philip et al., 2016), yet stands in contrast to results of Boggio et al. (2010) showing differential effects on mood versus anxiety symptoms during a 10-session course of 20 Hz rTMS based on laterality. We chose an “intermediate” frequency parameter, i.e., higher than 1 Hz but lower than 10 Hz, which might have accounted for the broader benefits observed in our patient sample. More research is needed to elucidate the therapeutic mechanisms of rTMS delivered across differing pulse frequencies, and how underlying neurobiological changes translate to narrow or broad domains of clinical improvement.

Several factors were associated with nonresponse. Greater depressive symptom severity predicted worse response, consistent with previously reported predictors of nonresponse to antidepressant medication (Kilts et al., 2009) and to rTMS in a large naturalistic sample that likely included patients with diagnostic comorbidities (Carpenter et al., 2012). Additionally, a greater degree of PTSD avoidance symptoms at baseline predicted inferior outcomes. The type of stimulation we applied in this trial may have been insufficient or counterproductive for engaging the circuitry associated with avoidance symptoms. Behavior therapy specifically targeting avoidance in concert with rTMS may be required to see benefit in this domain.

Strengths and limitations

A significant strength of this study is the focus on a patient population that has been excluded from rTMS registration trials yet commonly presents in treatment settings. The majority of participants were fully disabled due to their symptoms. In addition to improvements in both MDD and PTSD symptoms domains, we found rTMS significantly reduced subjective stress levels, as measured by the DASS and PSS. There was limited racial and ethnic diversity in our sample due to the demographic characteristics of patients in our clinical practice settings. However, individuals with both early childhood trauma as well as adult onset (combat exposure) were included. Except as noted above, we required medications to be stable, which reduces but does not eliminate the possibility that observed positive effects were attributable at least in some part to ongoing psychotropic medications. Use of concurrent medications may be considered a limitation when evaluating the efficacy of rTMS in any sample, but we identified a pressing need for data describing naturalistic outcomes to inform everyday clinical practice. Furthermore, we allowed ongoing concurrent psychotherapy to continue on a stable schedule during the trial, so it is possible our results also incorporated additive effects or synergy between rTMS and psychotherapy. The lack of a sham comparator limits our ability to attribute findings to stimulation with the highest level of confidence. Due to sample size, our exploration of clinical predictors of response was limited to correlational analyses of baseline severity ratings on clinical measures. Future studies, using larger sample sizes, will need to evaluate the impact of other potentially informative candidate clinical variables (e.g., trauma type, childhood vs. adult onset, duration of illness, baseline medication status). Other limitations include modest sample size, limitations inherent to retrospective assessments of trauma and symptom onset, and lack of assessments to detect impact of the treatment on quality of life or functional status.

Conclusions

The current study demonstrates the feasibility, safety and potential efficacy of 5 Hz rTMS for individuals with comorbid PTSD and MDD. Though they were not represented in the regulatory trials, many patients with this common clinical comorbidity appear to benefit from rTMS therapy and tolerate it well as an adjunct to psychotropic medications when delivered with a 5 Hz protocol.

Supplementary Material

Clinical highlights
Conflict of Interest Statement

DECLARATIONS OF INTEREST:

This study was funded in part by an investigator-initiated grant from Neuronetics, Inc. to Butler Hospital (Drs. Carpenter and Philip). Drs. Carpenter, Tyrka and Price have received grant support from Janssen, Neosync, and Cervel Neurotech through clinical trials contracts with Butler Hospital. Neosync and Neuronetics have provided devices for research underway by several coauthors. Dr. Carpenter has received consulting income from Magstim Ltd. Dr. Philip has served as an unpaid scientific advisory board member for Neuronetics. All other authors report no biomedical financial interests or potential conflicts of interest.

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Supplementary Materials

Clinical highlights
NIHMS1034053-supplement-Clinical_highlights.docx (10.3KB, docx)
Conflict of Interest Statement
NIHMS1034053-supplement-Conflict_of_Interest_Statement.docx (61KB, docx)

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