STRONG STAR and the Consortium to Alleviate PTSD (CAP)

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1 STRONG STAR and the Consortium to Alleviate PTSD (CAP) Presentation to: San Antonio Combat PTSD Conference, October 18-19, 2017 Presentation by: Sheila A.M. Rauch, Ph.D. Biological and Symptom Changes in PTSD Treatment

2 Biological and Symptom Changes in PTSD Treatment Presenter: Sheila A.M. Rauch, Ph.D. Emory University School of Medicine Atlanta VAMC Disclaimer: The views expressed in this presentation are solely those of the author(s) and do not reflect an endorsement by or the official policy or position of the U.S. Army, the U.S. Air Force, the Department of Defense, the Department of Veterans Affairs, or the U.S. Government. Funding: This article was based on work supported by a Career Development Award (CDA-2) from the VA Office of Research and Development Clinical Sciences Research and Development (PI: Rauch). Dr. Rauch has received grant funding from VHA and DOD. Dr. Liberzon has received grant funding from DOD & NIH.

3 What is a Treatment Mechanism? Factor that causes/drives treatment change(kazdin, 2007) Must be CAUSAL (Kazdin, 2007) Most likely many mechanisms at work in most effective PTSD treatment 3

4 Why Study TREATMENT mechanisms of change? Bring order/parsimony in treatment decision making and development Impact beyond mental health to larger biological system Optimize treatment outcomes Improve dissemination Better match patients to treatments To contribute to general knowledge base Kazdin,

5 Mechanisms of PTSD Treatment Prolonged Exposure (PE) Developed out of Emotional Processing Theory Other theories also have relevance: Fear learning and extinction Inhibitory learning Neurocircuitry models of PTSD Several mediators and moderatos of outcome have been identified though the requirement for a timeline to establish causation has rarely been met Rauch & Liberzon,

6 What mechanisms and biomarkers? Use measures with previous signal as possible mechanisms Related to PTSD symptom severity Related to PTSD symptom change in treatment or natural recovery Maximize efficiency in data collection, cost, and data qualitylook for low burden and high information yield measures Not interfere with recruitment Mechanisms selected: Trauma related cognitions HPA axis function Trauma potentiated Startle

7 Cognitions and PTSD Two related to the development, maintenance, and effective treatment of PTSD: the world is completely dangerous, and I am incompetent (i.e., I cannot handle stress, my symptoms mean I am crazy, etc.; Foa and Riggs, 1995). Confrontation of trauma related stimuli: Emotional responses are reduced Dysfunctional cognitions are disconfirmed. Foa & Kozak, 1986; Rauch & Foa,

8 Cognitions and PTSD Increased self-competence and control over negative affect leads to: reduced avoidance more spontaneous exposure, and continued reduction of PTSD symptoms. Change in PTSD related cognitions occurs in PE even without specific CR intervention (i.e., Foa & Rauch, 2004). Reductions in negative thoughts about the self and the world are associated with symptom improvement (Foa & Rauch, 2004). 8

9 PTSD and HPA Axis Hypothalamic-pituitary adrenal (HPA) axis is disrupted in PTSD Normalization of HPA axis may be associated with symptom improvement Little research has examined how HPA axis function changes over the course of treatment Results have been inconsistent often due to methodological variations 9

from Yehuda 2001 Posttraumatic Stress Disorder is associated with abnormalities in stress systems: CRH ACTH Cortisol Sympathetic / Adrenergic: Exaggerated Psychophysiology Responses (HR, SCR) to

10 from Yehuda 2001 Posttraumatic Stress Disorder is associated with abnormalities in stress systems: CRH ACTH Cortisol Sympathetic / Adrenergic: Exaggerated Psychophysiology Responses (HR, SCR) to trauma cues HPA Axis: Elevated CRH secretion Hypo-cortisolemia Hyper-cortisolemia No change in cortisol Increased feedback inhibition (increased suppression in DST) Exaggerated HPA axis responses to Trauma Recall? Summary Slide Borrowed from Anthony King, Ph.D. 10

11 Trauma Potentiated Startle PTSD patients show: Increased startle to anxiety provoking aspects of experimental context (Grillion & Morgan, 1999; Grillon, et al, 1998; Grillon et al, 2009) Heightened response during fear expression (Norrholm, et al, 2011) Rothbaum et al (2014) demonstrated: Higher baseline startle response predicted larger response to exposure therapy for veterans who received DCS (not alprazolam or placebo; Norrholm, et al, 2016) Reductions in startle response during VR following treatment for veterans who received DCS (not alprazolam or placebo) 11

12 Study Aims Pilot data for larger RCT of PE vs. PCT in OEF/OIF veterans Determine controlled effect size Portability of protocol Active Control- What does exposure add to good PTSD focused psychotherapy? Examine potential mechanisms of change and their interrelationships Cognitive HPA axis function Trauma Potentiated Startle 12

13 Participants 30 combat veterans randomly assigned to: PE PCT Inclusion- OEF/OIF with combat related PTSD of at least 3 months duration Exclusion any current level of personality disorder or suicidal risk that makes PTSD treatment unwarranted at this time substance dependence in last 3 months Psychosis/ mania Working night shift Less than 4 weeks on stable meds taking medication that makes HPA axis measures difficult to interpret Unmedicated bipolar 13

14 Overall Design & Methods Random assignment to PE or PCT Major assessments at pre, mid (before session 6), post, 3 months, 6 months Retreated after sessions if desired (many before 3/6 mo fu) CAPS reduction of 50% or more = High responder

15 Challenge Tasks Cortisol Awakening Response (awaken, 30min, 45min) Script driven imagery w/psychophys and cort (90 min.) Fear potentiated startle paradigm w/ psychophys (15 min) In session cort sessions 3, 6, and 10 w/3 tubes per session (start of session, 45 minutes into the session, and at the end of the session)

16 Sample Demographics (N = 30) % % Male 91.7 MDD 58.3 Caucasian 83.3 Alcohol Abuse 16.7 Working Full/PT 58.3 Substance Abuse 2.8 Afghanistan 22.2 SC for PTSD 13.9 Iraq 86.1 Completers 61.1 Married 55.5 Drop/ Withdrawn/ Early Responder 38.9 Mean Age (SD) 32 (7.6) Non-starters 16.7 Mean Yrs Education 13.3 (1.7) Withdrawn

17 CHANGE IN CAPS (COMPLETERS) PCT PE 0 Pre (n = 22) *Mid (n = 22) *Post (n = 22) Time*Condition, F (1.5, 29) = 5.9, p =.01; Hedges g =.79; Rauch et al, 2015

18 Comparison of Responder Status by Condition Responder defined as 50% or more reduction in CAPS from pre to post PE = 47% PCT = 14% χ 2 = 4.6, p =.03 Rauch et al,

19 Change in PTSD and Cognitions (n = 28- ITT) Self World Self-Blame CAPS Total.70**.38 x.52** Reexperiencing.51** Avoidance.77**.43 x.52** Hyperarousal.65**.33.59* ** p <.0001; * p <.001; x p <.05; Rauch et al,

20 20 RESPONDERS COMPARISON OF PTCI- SELF Responder NonResponder Pre (n = 28) Mid (n = 28) Post (n = 28) Time F (1.4, 29.4) =.14.6, p <.0001; Time*Responder F (1.4, 37.6) =, p <.0001; Rauch et al, 2015

21 Cognitions Summary Responders have larger reductions in PTSD related cognitions, especially negative thoughts about the self. Reductions in Negative Thoughts about the self and world are closely related to reductions in all PTSD symptoms. Reduction in negative thoughts about the self and world cognitions drives PTSD symptom change in PE (Kumpula, Rauch, et al., 2016; Zalta, et al, 2014). 21

22 SCRIPT DRIVEN IMAGERY: PRE 22 saliva cortisol Neutral: Cortisol response scripts: time 1 pre-therapy Neutral Tx responder n=8 Tx nonresponder n=20 Trauma Trauma: 0 RT-ANOVA: time p =.02 t*cond p = ns min Rauch et al, 2015

23 CORTISOL RESPONSE TO TRAUMA SCRIPT (PRE) AND CAPS CHANGE Improvement in CAPS r(21) = 0.44, p< Cortisol Response AUCi - Trauma Script Rauch et al, 2015

24 CAR CORTISOL IN PE VS PCT 24 Effect of therapy type (PE vs PCT) on Cortisol Response to Awaking Cortisol Response to Awakening (AUCtot) PE (n=7) PCT (n=10) Group effect F[1.15]=11.4, p=.004 pre mid Follow-up post Rauch et al, 2015

25 Within Session Cortisol Reactivity by Responder Rauch, et al., In Press 25

26 In Session Cortisol Responder status significantly predicted slope of cortisol level across sessions (β=-1.35, t=-2.10, p=.04) Responder status accounted for 6% of the previously unexplained variance in cortisol level Rauch, et al.,

27 Cortisol Summary PRETREATMENT PREDICTOR Higher cortisol response to trauma script pre-treatment predicted PTSD symptom reduction. PE showed more normalization of CAR than those receiving PCT. People who go on to have LOW and HIGH response to therapy DO NOT look different in the first PE session cortisol collection (session 3). LOW RESPONDERS show increases in IN THERAPY session cortisol reactivity. High responders show little change in IN THERAPY session cortisol reactivity. Rauch et al, 2015; Rauch et al.,

28 Trauma Potentiated Startle Robison-Andrew, Duval, Nelson, Echiverri-Cohen, Giardino, Defever, Norrholm, Jovanovic, Rothbaum, Liberzon, Rauch,

29 Overall Summary Both PE and PCT reduce PTSD severity in Veterans PE results in significantly larger reductions and more remission than PCT. Responders have larger reductions in Negative thoughts about the self that are closely related to PTSD symptom reductions. Complexity of the HPA axis system in PTSD remains clear with this study PRETREATMENT PREDICTOR Higher cortisol response to trauma script pre-treatment predicted PTSD symptom reduction. PE showed more normalization of CAR than those receiving PCT. 29

30 Overall Summary A different pattern is apparent during therapy. People who go on to have LOW and HIGH response to therapy do not look different in the first session cortisol collection (session 3). LOW RESPONDERS show increases in IN THERAPY session cortisol reactivity. High responders show little change in IN THERAPY session cortisol reactivity. Sample size is small and replication is needed. 30

31 NEXT STEPS Replication and extension in larger samples!!!!! How do these effects relate to each other? How do these effects relate to other levels of examination (such as emotion processing and regulation using imaging)? A multi-site RCT examining PE, SERT, and combination examining in 223 OEF/OIF/OND Veterans: Symptom change/effectiveness emotion processing and regulation in fmri paradigms Genetics and genomics CAR 31

32 Extra stuff 32

33 CHANGE IN CAPS (COMPLETERS) PCT PE 0 Pre (n = 22) *Mid (n = 22) *Post (n = 22) Time*Condition, F (1.5, 29) = 5.9, p =.01; Hedges g =.79; Rauch et al, 2015

Sheila A.M. Rauch, Ph.D., ABPP

Sheila A.M. Rauch, Ph.D., ABPP Atlanta VAMC Emory University School of Medicine Disclaimer: The views expressed in this presentation are solely those of the authors and do not reflect an endorsement by