Research paperRepetitive TMS to augment cognitive processing therapy in combat veterans of recent conflicts with PTSD: A randomized clinical trial
Introduction
Posttraumatic Stress Disorder (PTSD) is a major military and civilian public health problem. The National Co-morbidity Survey (NCS) reported a lifetime prevalence rate of 7.8% for PTSD in a national sample (Kessler et al., 2005, Kessler et al., 1995), while the data from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions found the lifetime prevalence of PTSD to be 6.4% (Pietrzak et al., 2011). The National Vietnam Veterans Readjustment study reported that 31% of males and 27% of females met full criteria for PTSD using DSM-IV-TR criteria over their lifetime (n = 3016) and that 15% of males and 9% of females met full criteria for PTSD at the time of the study (Kulka et al., 1990). The more recent National Vietnam Veterans Longitudinal Study demonstrated that between 4.5–11.2% of males and 6.1–8.7% of females suffer from current war-zone PTSD depending on the assessment method utilized (Marmar et al., 2015). With respect to veteran deployments, 15.6–17.1% of those deployed to Iraq and 11.2% of those deployed to Afghanistan met screening criteria for PTSD, major depression, or general anxiety disorder upon return (Hoge et al., 2004). Another study found estimated prevalence rates of PTSD based on DSM-IV symptoms were from 20.7% to 30.5% at 3 and 12 months post deployment (Thomas et al., 2010). More recently, a meta-analysis estimated prevalence of PTSD from deployments to Iraq and Afghanistan to be 23% (Fulton et al., 2015). In addition to being a common sequela of deployment to combat regions, PTSD results in significant functional impairment (Rodriguez et al., 2012, Shea et al., 2010).
Evidence based psychotherapies such as prolonged exposure (PE) and cognitive processing therapy (CPT) are supported by clinical research with veteran, active duty military personnel, and civilian samples (Foa et al., 1999, Rauch et al., 2009, Resick et al., 2002, Resick et al., 2017, Schnurr et al., 2007). These treatments are also recommended in the VA/DOD Clinical Practice Guidelines for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder 2017 and by the Institute of Medicine (IOM Institute of Medicine, 2014). However, many individuals have difficulty completing these therapies (Miles and Thompson, 2016, Najavits, 2015, Niles et al., 2017, Steenkamp et al., 2015). Furthermore, a recent review of randomized clinical trials for military-related PTSD demonstrated that although these therapies do result in meaningful improvement in patients with PTSD, approximately two-thirds of patients continued to meet full criteria for PTSD (Steenkamp et al., 2015). Thus, new treatment approaches or approaches that augment the benefits of PE and CPT are critically needed to improve treatment outcomes.
Cognitive Processing Therapy (CPT) was originally developed to treat victims of sexual assault (Resick and Schnicke, 1992) and has been revised specifically for combat veterans with PTSD within the VA Healthcare system. The Cognitive Processing Therapy Veteran Military Version manual (2007) was utilized for this study (Monson et al., 2006). CPT is a trauma-focused therapy that combines elements of exposure and cognitive therapy to reduce PTSD symptoms and associated symptoms such as depression, anxiety, guilt, and shame. CPT involves eliciting memories of traumatic events and directly confronting conflicts and maladaptive beliefs associated with those memories (Resick and Schnicke, 1992). The therapy also seeks to facilitate the expression of the appropriate affect associated with the trauma while assisting the patient with the development of an alternative view of the trauma that is balanced and realistic as well as the modification of extreme beliefs or cognitions that prevent the individual from having disconfirming experiences.
Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and non-invasive technique that has demonstrated promise and effectiveness in treating a number of neuropsychiatric conditions including Major Depressive Disorder (Gaynes et al., 2014, George et al., 2010, Kozel and George, 2002, O'Reardon et al., 2007). Although not definitive, there is growing evidence that the symptoms of PTSD can be ameliorated by rTMS (Berlim and Van Den Eynde, 2014, Boggio et al., 2010, Clark et al., 2015, Cohen et al., 2004, Grisaru et al., 1998, Karsen et al., 2014, McCann et al., 1998, Nam et al., 2013, Oznur et al., 2014, Philip et al., 2016, Rosenberg et al., 2002, Watts et al., 2012). Relevant to the current study, 1 Hz stimulation applied over the prefrontal cortex produced an inhibitory effect on the subjacent brain structures (Kozel et al., 2009, Speer et al., 2000), including reduction of the event-related potential (ERP) P3a hyperarousal response to combat-relevant threatening stimuli in PTSD (Tillman et al., 2011). PTSD patients also have shown increased amygdala response when engaged in PTSD-related script-driven imagery (Rauch et al., 1996, Shin et al., 1997) and when shown fearful stimuli (Rauch et al., 2000), suggesting dysfunctional amygdala hyperactivation. Importantly, rTMS administered to right dorsolateral prefrontal cortex (rDLPFC) has been shown to decrease amygdala activation to threatening stimuli (Baeken et al., 2010).
There also have been studies that have combined rTMS with exposure psychotherapy as well as script driven imagery. Osuch et al. 2009 (n = 9) combined exposure therapy with either 1 Hz or sham rTMS and found moderate improvement in hyperarousal symptoms on the clinician-administered PTSD scale (CAPS) with exposure plus active rTMS; however, the difference between active and sham was not significant (Osuch et al., 2009). Isserles et al. tested (n = 30) an H-coil also called Deep TMS (DTMS) with script driven imagery from a traumatic event to relieve the symptoms of PTSD. DTMS after imagery of traumatic experience demonstrated a significant improvement in the intrusive component of the CAPS score and a trend for improvement in the total CAPS score. Conversely, the DTMS after imagery of positive experience group and the sham DTMS after imagery of traumatic experience group demonstrated no significant improvement (Isserles et al., 2013). (See Supplementary information for rTMS studies in PTSD and rational for rTMS parameters.)
Overall, the studies combining rTMS with re-exposure or script-driven imagery showed improved symptom reduction with the addition of rTMS or resulted in no “significant” change in symptoms. There are no studies demonstrating worsening of symptoms. Also, several meta-analyses have shown rTMS alone to lead to symptom reduction in PTSD (Berlim and Van Den Eynde, 2014, Karsen et al., 2014, Trevizol et al., 2016). With these studies and our finding that 1 Hz right DLPFC rTMS resulted in significant reduction in ERP P3 hyperarousal response to combat threatening stimuli in PTSD, we hypothesized that right prefrontal 1 Hz rTMS would work synergistically with CPT to reduce PTSD symptoms in combat veterans. To test our hypothesis, we used a parallel design in which we randomized veterans with combat related PTSD to active versus sham [1:1 ratio] 1 Hz rTMS to right prefrontal cortex just prior to CPT. The Clinician Administered PTSD Scale (CAPS) served as the primary outcome measure of PTSD symptom severity. The PTSD Checklist (PCL), the Mississippi Scale for Combat Related PTSD (M-PTSD), the Quick Inventory of Depressive Symptomatology (QIDS), and the Inventory of Psychosocial Functioning (IPF) served as additional measures. The treatment schedule of rTMS was determined by the standard treatment schedule of CPT, as rTMS was delivered just prior to each CPT session.
Section snippets
Participants
Veterans previously deployed to combat regions from 2001 to present (e.g., Operation Enduring Freedom (OEF), Operation Iraq Freedom (OIF), and Operation New Dawn (OND)) with current combat-related PTSD symptoms were recruited from the community (ClinicalTrials.gov NCT01391832). Recruitment focused on military installations, Veteran Affairs Hospitals, Veteran Centers, local universities and colleges with veteran enrollment, and various non-profit veteran associated service organizations.
Results
Five hundred fifteen individuals were contacted or inquired about participating in the study; of whom 103 participants were randomized to either the active or sham rTMS (rTMS+CPT n = 54, sham+CPT n = 49) (see Fig. 1). One participant in the rTMS+CPT group was considered by the assessors to have given responses with substantially reduced validity on CAPS at baseline (i.e., Global Validity = 3), although acceptably valid responses were given at all other assessment sessions. Thus, this
Discussion
The addition of rTMS to CPT produced greater PTSD symptom reduction compared to sham+CPT. The strength of the effect, however, did differ across PTSD measures. Both the rTMS+CPT and sham+CPT groups showed statistically significant improvements in clinician (i.e., CAPS) and patient (i.e., PCL) rated symptom severity. However, although patient-rated symptom severity for the rTMS+CPT was statistically significantly lower at all assessment periods compared to the sham+CPT group, clinician rated
Conclusions
Combining CPT with rTMS led to improved symptom reduction in combat veterans with PTSD. Thus, the results show that rTMS combined with psychotherapy can augment the benefits of psychotherapy alone and improve treatment outcomes. Further work, however, is required before this treatment approach can be considered as standard clinical care.
Acknowledgments
This work was supported by Department of Defense Grant W81XWH-11-2-0132 and Texas Health and Human Services Commission HHSC Contract 529-14-0084-00001. We wish to thank Dr. Susan Schultz for her review and thoughtful comments on this manuscript.
Disclaimer statement
The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of Defense, the Department of Veteran Affairs, or the U.S. Government. Neither the James A. Haley VAH nor VA health care providers were involved with this study during VA duty time.
Role of the funding source
DOD – provided review and funding of grant. Approval of study was obtained through Army Human Research Protection Office. Otherwise, the sponsor had no role in design, implementation, analysis, conclusion, or manuscript preparation/editing of this study.
Texas Health and Human Services Commission – provided review and funding of grant. Otherwise, the sponsor had no role in design, implementation, analysis, conclusion, or manuscript preparation/editing of this study.
Financial disclosures
F. Andrew Kozel – I do not
Trial registration
clinicaltrials.gov; NCT01391832; Novel Treatment of Emotional Dysfunction in Post Traumatic Stress Disorder (PTSD); https://clinicaltrials.gov/ct2/show/NCT01391832.
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Location of Work: University of Texas at Dallas, Dallas, TX, USA.