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 RESEARCH ARTICLE

Interfering with the reconsolidation of traumatic memory: Sirolimus as a novel agent for treating veterans with posttraumatic stress disorder

Alina Surís, PhD, ABPP

VA North Texas Health Care System, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

Julia Smith, PsyD

VA North Texas Health Care System, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

Craig Powell, MD, PhD

Department of Psychiatry, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Carol S. North, MD, MPE

VA North Texas Health Care System, Departments of Psychiatry and Surgery/Division of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

BACKGROUND: Development of novel treatment approaches for combat-related posttraumatic stress disorder (PTSD) is critical, given the increasing prevalence of PTSD in veterans returning from war zone deployment. Established preclinical research using protein synthesis inhibitors (such as sirolimus) to interfere with fear memory reconsolidation provides a compelling rationale for investigation in humans.

METHODS: This double-blind, placebo-controlled translational pilot study examined the effects of pairing reactivation of a trauma memory with a single administration of sirolimus on the frequency and intensity of PTSD symptoms in male combat veterans.

RESULTS: Primary analyses found no significant differences between treatment groups on any of the clinical or physiologic outcome measures. In an exploratory analysis of a subsample of post–Vietnam-era veterans who had more recent combat trauma, PTSD symptom scores fell significantly more in these veterans than in controls.

CONCLUSIONS: The post–Vietnam-era veteran findings suggest that further investigation of this pairing of sirolimus with traumatic memory reactivation may be warranted. Theoretically, interference with the reconsolidation of fear memories could ameliorate military-related psychological trauma symptoms. Future research should focus on veterans of more recent eras whose traumatic memories may be less entrenched and more amenable to pharmacologic modification within this procedure.

KEYWORDS: posttraumatic stress disorder, memory, veterans, memory reconsolidation, novel intervention, trauma, pharmacotherapy

ANNALS OF CLINICAL PSYCHIATRY 2013;25(1):33-40

  INTRODUCTION

Posttraumatic stress disorder (PTSD) is an anxiety disorder characterized by the development of intrusive memories, nightmares, and flashbacks after exposure to a traumatic event.1,2 Intrusive reexperience is fundamental to the commencement and maintenance of posttraumatic symptoms over time. Animal studies of memory consolidation have demonstrated that all new memories are maintained in short-term memory until they are transferred at the cellular level into long-term storage. This consolidation is necessary for the development of stable long-term memory of a traumatic event. The memory can again become malleable if it is reactivated. Reactivation involves the retrieval of a consolidated memory from long-term storage, rendering the memory trace labile until it is reconsolidated to long-term memory for more permanent storage.3 This lability of memory during reconsolidation may offer a biological window during which long-term memories can be influenced. Thus, reconsolidation is an important mechanism for updating or modifying memories.4 Memory reconsolidation provides a potential leverage point for chemotherapeutic interventions: the pathologic memories associated with PTSD may be modified to yield more adaptive memories.

Preclinical studies have begun to unravel the neurobiological mechanisms of memory consolidation and reconsolidation. Glucocorticoids and protein synthesis inhibitors such as anisomycin have been shown to block processes necessary for memory reconsolidation.5-8 Unfortunately, anisomycin’s toxicity makes it prohibitive for therapeutic use in humans.

A safer alternative for inhibiting reconsolidation of an established trauma memory may be to selectively target the subset of protein translation needed for synaptic plasticity. In preclinical studies, this has been accomplished with the use of rapamycin.9 Rapamycin regulates dendritic protein synthesis in the amygdala and dorsal hippocampus through the systemic inhibition of the protein kinase mTOR (mammalian target of rapamycin) pathway.9 Administration of rapamycin has been shown to reduce reconsolidation of fear memories in animals in a contextual fear conditioning paradigm.10 A single dose of rapamycin administered in conjunction with a memory reactivation procedure produced lasting reduction of the contextual fear memory.

The animal study findings provide a compelling rationale for conducting analogous studies of memory reconsolidation in humans. The goal is to identify a novel method for reducing the emotionally intense traumatic memories characteristic of PTSD through pairing rapamycin with memory reactivation. For human use, this compound is known as sirolimus. Originally developed as an antifungal agent, sirolimus is prescribed for its immunosuppressant properties, especially for patients undergoing renal transplantation.11

The aim of this translational pilot study was to examine the effects of a single procedure, ie, pairing reactivation of a specific trauma memory with administration of sirolimus in a double-blind, randomized, placebo-controlled trial, on the frequency and intensity of PTSD symptoms in male combat veterans. It was hypothesized that this procedure, compared with placebo, would result in: 1) reduced frequency and intensity of PTSD symptoms 1 and 3 months posttreatment, and 2) reduced intensity of trauma-related physiologic responses to the trauma memories.

  METHODS

The research protocol was approved by the institutional review board of a large southwestern Veterans Affairs (VA) Medical Center. After a comprehensive explanation of the procedures, all study participants provided written informed consent.

Sample

Potential participants were recruited through flyers, clinician referrals, and letters mailed to patients with current PTSD, as identified through VA medical records. Inclusion criteria were: male sex, a PTSD diagnosis in the patient’s medical record, and enrollment in mental health services at the VA Medical Center. Exclusion criteria were: hypersensitivity to sirolimus, current use of medications with potential drug interactions with sirolimus, medical conditions known to be associated with adverse effects with sirolimus use (eg, systemic infections, congestive heart failure, renal or hepatic failure, malignancy, pulmonary fibrosis, and brain damage, including unresolved sequelae of a traumatic brain injury), substance dependence in the last 3 months, current suicidal or homicidal ideation, and currently receiving immunosuppressive therapy. Patients were not allowed to participate in the study while undergoing psychotherapy specific to PTSD treatment. Patients on stable doses of psychotropics were not excluded. A total of 54 eligible participants were randomized to treatment groups (sirolimus vs placebo).

Instruments of measure

The Clinician-Administered PTSD Scale (CAPS) was administered to verify the PTSD diagnosis and assess symptom severity of participants’ most distressing military trauma. CAPS measures the frequency and intensity of the 17 DSM-IV-TR PTSD symptoms on a behaviorally anchored 5-point rating scale from 0 (“never”) to 4 (“daily or almost daily”). Its psychometric properties have been demonstrated to be acceptable.12 A reduction of CAPS score by 20 points was considered to represent a clinically meaningful symptom improvement.13 The CAPS provides not only a total PTSD symptom score but also scores for symptoms corresponding to DSM-IV-TR groups B, C, and D PTSD criteria.

The PTSD Checklist (PCL) and Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-SR) provided subjective levels of posttraumatic and depressive symptoms, respectively. The PCL is a brief self-report inventory that assesses level of distress associated with the 17 DSM-IV-TR symptoms of PTSD in the intrusion (group B), avoidance/numbing (group C), and hyperarousal (group D) symptom groups, and in this study the assessment of these symptoms was keyed to the combat trauma incident identified by participants during administration of the CAPS.14 The QIDS-SR is a brief self-report inventory for assessing 16 DSM-IV depressive symptoms.15 The psychometric properties of the PCL16 and QIDS-SR17 have been demonstrated to be acceptable.

Dosing of sirolimus

A 15-mg dose of sirolimus was chosen because the customary loading dose of sirolimus is 15 mg, and up to 40 mg/d is used for treating medical conditions in humans.18 Possible side effects of chronic sirolimus administration include cancer, headaches, insomnia, gastrointestinal symptoms, increased susceptibility to infection, and renal function changes. There is no available information on side effects of 1-time administration. Most potentially serious side effects require accumulation of the medication in the bloodstream through steady-state pharmacokinetics; therefore, toxic effects were not anticipated with a single dose. Regardless, participants were monitored for potential adverse medical outcomes or side effects, but none occurred in this study.

Procedures

Participants completed the study’s procedures over 5 sessions, as described below.

Baseline assessment (session 1). Demographic information was recorded and the CAPS, PCL, and QIDS-SR were administered. These assessments were administered by a licensed, doctoral-level psychologist or a master’s-level clinician under the supervision of a licensed, doctoral-level psychologist.

Study medication and traumatic memory reactivation (session 2). An oral dose of sirolimus or placebo was administered in a double-blind fashion. After taking the study medication, participants were guided through an established script-preparation procedure in which they described their most distressing combat trauma incident in writing on a standard script preparation form.19 Participants also were asked to select from a standard list of commonly experienced bodily responses during trauma that they experienced during the incident (eg, racing heart, sweaty palms, breathing fast, etc.). The average time between administration of the study medication and completion of these tasks was 45 minutes (range, 30 to 75 minutes). Participants then completed the QIDS-SR and PCL.

From the information gathered during the script-preparation procedure, a script of approximately 120 words (30 to 40 seconds in duration) describing the participants’ combat trauma incident was composed, incorporating 5 of the participants’ bodily responses. These scripts were read aloud and audio recorded by a male project staff member for use during session 3. A representative composite example of a combat-trauma script is provided below:

    It’s March 2007; you’re in Iraq. You’re in your living quarters, right outside Highway 1. Suddenly an IED [improvised explosive device] hits a vehicle that has 4 soldiers in it. The explosion shakes everything. Your adrenaline kicks in. Your heart is pounding as you react quickly, thinking, “What can I do?” You go outside to gather troops for rescue efforts. You see the vehicle burning; the soldiers are screaming inside. You feel helpless because there is nothing you can do to get to them; the fire is burning too hot. You’re hot and sweaty all over. It’s hard to breathe. Your back is in pain from the tension. You feel drained, and your head pounds.

Physiologic assessment (session 3). Seven days after session 2, participants underwent a script-driven imagery procedure.19 Participants were familiarized with the laboratory and equipment, and recording electrodes were placed on the participants. Three scripts were presented to the participants through headphones: first, a standard neutral script (eg, description of sitting on a lawn chair); next, the personal combat script; and finally, another standard neutral script. Participants were instructed to listen carefully to the script and imagine that they were currently experiencing the incident. Heart rate, skin conductance, and facial muscle activity (left lateral frontalis and corrugator electromyograms) were recorded using the Coulbourn LabLinc V Human Measurement System (Coulbourn Instruments). At the end of the session, participants completed the QIDS-SR and PCL.

One-month and 3-month follow-up assessments (sessions 4 and 5, respectively). At these sessions, the CAPS, QIDS-SR, and PCL were administered to assess current symptom levels.

Statistical analysis

One participant had missing data and 2 additional participants had invalid CAPS scores and were excluded from the analyses, yielding a total sample of 51 participants. Change scores for physiologic measures from baseline to postscript periods were calculated separately for each script presentation. A log transformation was used to reduce skewness and heteroscedasticity of these measures. t tests for independent samples were used to compare group differences on clinical outcome measures and physiologic measures. The 2 treatment groups were compared for clinically meaningful improvement in PTSD symptoms (defined, for our purposes, as a 20-point reduction in the CAPS total score, which is a more conservative threshold for clinically significant change than previously suggested).20 A repeated-measures analysis of variance was used to compute between- and within-individual effects on the clinical outcome measures over time. Comparison of treatment group proportions demonstrating clinically meaningful improvement was done with Fisher exact tests. Level of statistical significance was set at α=.05. Lastly, to facilitate exploration of potential differences in treatment outcome based on recency of combat exposure, the sample was broken down into 2 subgroups: Vietnam-era veterans (served in the military between February 28, 1961 and May 5, 1975; n=17) and post–Vietnam-era veterans (served in the military after May 8, 1975; n=34). The above comparisons were repeated with these subgroups.

  RESULTS

Characteristics of the sample are listed in TABLE 1. The combat-era groups did not differ significantly on any demographic variable. Compared with the Vietnam-era group, the post–Vietnam-era group had a significantly greater age of PTSD onset and significantly fewer years of PTSD duration.

TABLE 2 shows the results of psychological measures at baseline and follow-up visits by treatment group for all participants and the Vietnam and post-Vietnam groups. For the entire sample, no significant findings on any of these measures were observed between the sirolimus (n=27) and placebo (n=24) groups at any single time point (ie, at baseline and follow-up assessments), and no differences in these measures across time were found between the treatment groups. Clinically meaningful symptom improvement was observed in 40% (11/27) of the sirolimus group vs 16% (4/24) of the control group at the 1-month follow-up (Fisher exact P=.067) and in 44% (12/27) vs 29% (7/24) at the 3-month follow-up (Fisher exact P=.14).

There were no significant differences between treatment groups on any physiologic variables for either the combat-related or neutral scripts (not shown in TABLES). During the study procedures, the mean (SD) heart rate was 71.56 (10.20) bpm at the completion of the neutral baseline script; it decreased by 0.51 (3.34) bpm after presentation of another neutral script (P > .05), and increased by 4.99 (5.27) bpm after presentation of the trauma script (t=-5.00; df=49; P < .001). Similarly, mean (SD) skin conductance was 3.20 (4.03) μs with the neutral baseline script, decreased by 0.04 (0.28) μs after presentation of another neutral script (P > .05), and increased by 0.83 (1.31) μs after presentation of the trauma script (t=-3.99; df=34; P < .001). Therefore, heart rate and skin conductance changed little with a neutral script and both increased significantly with the trauma script, reflecting a physiologic response to the trauma script that was not observed with the neutral script.

The clinical outcome variables were further examined for the Vietnam and post-Vietnam subgroups separately (TABLE 2). There were no significant baseline differences between the sirolimus- and placebo-treated participants for either subgroup on any of the measures. There were no significant differences in depressive symptom scores (QIDS-SR) or any of the physiologic measures at any time for either subgroup.

Within the Vietnam-era subgroup, no significant differences were observed between treatment groups on any of the clinical or physiologic outcome measures and no significant differences were found in the proportions showing clinically meaningful improvement at 1 or 3 months. However, in the post-Vietnam subgroup the sirolimus-treated group had significantly lower scores than the placebo-treated participants for the CAPS total and group D symptom scores and the PCL score at 1 month (TABLE 2). None of these differences persisted at 3 months. Clinical improvement was found in 47% (9/19) of the sirolimus group compared with 20% (3/15) of the placebo group in the post–Vietnam-era subgroup. These differences, however, were nonsignificant at both 1-month (Fisher exact P=.145) and 3-month (Fisher exact P=.152) follow-up assessments.


TABLE 1

Characteristics of the sample and era subgroups

  Entire sample
(N=51)
Vietnam
(n=17)
Post-Vietnam
(n=34)
DEMOGRAPHIC CHARACTERISTIC
Age (years), mean (SD)
  43.02 (14.91) 61.76 (1.88) 33.65 (7.98)
Education (years), mean (SD)
  13.84 (1.47) 14.00 (1.76) 13.76 (1.32)
Marital status, n (%)
Single, never married 6 (11.8%) 0 (0.0%) 6 (17.6%)
Married/cohabitating 31 (60.7%) 12 (70.6%) 19 (55.8%)
Divorced/separated 13 (35.4%) 4 (23.5%) 9 (26.4%)
Widowed 1 (1.9%) 1 (5.9%) 0 (0.0%)
Ethnicity, n (%)
White, non-Hispanic 24 (47.1%) 7 (41.2%) 17 (50.0%)
Black/African American 16 (31.4%) 8 (47.1%) 8 (23.5%)
White, Hispanic 3 (5.9%) 1 (5.9%) 2 (5.9%)
Black/African American, Hispanic 4 (7.8%) 0 (0.0%) 4 (11.8%)
American Indian 1 (2.0%) 1 (5.9%) 0 (0.0%)
Other 3 (5.9%) 0 (0.0%) 3 (8.8%)
Employment status, n (%)
Employed full-time 10 (19.6%) 1 (5.9%) 9 (26.5%)
Employed part-time 6 (11.8%) 1 (5.9%) 5 (14.7%)
Retired 11 (21.6%) 9 (52.9%) 2 (5.9%)
Unemployed 17 (33.3%) 3 (17.6%) 14 (41.2%)
Other 7 (13.7%) 3 (17.6%) 4 (11.8%)
Branch of Armed Forces, n (%)
Air Force 1 (2.0%) 1 (5.9%) 0 (0.0%)
Army 33 (64.7%) 11 (64.7%) 22 (64.7%)
Navy 3 (5.9%) 1 (5.9%) 2 (5.9%)
Marines 11 (21.6%) 4 (23.5%) 7 (20.6%)
Multiple (>1 branch) 3 (5.9%) 0 (0.0%) 3 (8.8%)
PTSD CHARACTERISTICS
Age of onset, mean (SD)
  24.61 (6.38) 20.53 (1.97) 26.65 (6.85)a
Illness duration (years), mean (SD)
  18.38 (16.83) 41.15 (1.15) 6.99 (5.29)b
Illness severity (baseline CAPS frequency, intensity, and total scores), mean (SD)
CAPS frequency score 36.88 (8.70) 36.35 (8.46) 37.15 (8.97)
CAPS intensity score 34.45 (8.30) 33.47 (9.82) 34.94 (7.54)
CAPS total score 71.33 (15.73) 69.82 (17.09) 72.09 (15.21)
at=–4.82; df=42.4; P < .001.
bt=35.96; df=38.8; P < .001.
CAPS: Clinician-Administered PTSD Scale; PTSD: posttraumatic stress disorder.

TABLE 2

Results of clinical outcome measures by treatment group (sirolimus, n=27; placebo, n=24) for all veterans (N=51), for the Vietnam veteran cohort (n=17) and for the post-Vietnam veteran cohort (n=34)

      Mean (SD)
  Score Treatment group Baseline 1-month follow-up 3-month follow-up
CAPS
All Total Sirolimus 72.13 (15.27) 58.27 (22.96) 55.26 (22.62)
Placebo 70.63 (16.37) 64.54 (17.88) 62.63 (17.60)
Group B Sirolimus 18.96 (6.00) 15.19 (8.33) 13.11 (7.73)
Placebo 19.29 (6.43) 17.50 (8.39) 17.08 (7.44)
Group C Sirolimus 27.22 (8.89) 21.62 (12.42) 21.41 (11.96)
Placebo 27.96 (9.25) 25.42 (8.16) 23.75 (8.69)
Group D Sirolimus 24.81 (4.70) 20.15 (5.74) 20.74 (20.74)
Placebo 24.96 (4.83) 21.63 (5.43) 21.96 (6.11)
Vietnam Total Sirolimus 74.88 (18.91) 70.75 (23.15) 56.38 (21.54)
Placebo 65.33 (14.94) 56.44 (10.85) 56.44 (15.27)
Group B Sirolimus 19.00 (5.92) 19.38 (4.74) 12.50 (6.90)
Placebo 17.00 (5.36) 14.89 (5.39) 15.11 (4.64)
Group C Sirolimus 30.38 (12.60) 22.50 (14.72) 23.63 (13.67)
Placebo 25.11 (12.43) 22.56 (10.08) 22.44 (10.30)
Group D Sirolimus 25.50 (4.87) 23.75 (5.72) 20.25 (6.29)
Placebo 23.22 (5.42) 19.00 (3.60) 18.89 (7.02)
Post-Vietnam Total Sirolimus 68.84 (15.39) 52.72 (21.93)a 54.79 (23.61)
Placebo 76.20 (14.43) 69.40 (19.76) 66.33 (18.35)
Group B Sirolimus 18.95 (6.20) 13.33 (8.99) 13.37 (8.22)
Placebo 20.67 (6.78) 19.07 (9.59) 18.27 (8.64)
Group C Sirolimus 25.89 (6.80) 21.22 (11.71) 20.47 (11.44)
Placebo 29.67 (6.64) 27.13 (6.55) 24.53 (7.85)
Group D Sirolimus 24.53 (4.74) 18.56 (5.12)b 20.95 (7.15)
Placebo 26.00 (4.29) 23.20 (5.83) 23.80 (4.84)
PCL
All   Sirolimus 57.19 (10.61) 49.62 (13.14) 51.07 (13.81)
Placebo 60.83 (10.26) 55.00 (11.85) 54.13 (11.23)
Vietnam   Sirolimus 60.88 (8.77) 58.13 (12.36) 56.38 (13.79)
Placebo 61.00 (9.59) 55.11 (13.67) 52.00 (10.82)
Post-Vietnam   Sirolimus 55.63 (11.14) 45.83 (11.09)c 48.84 (13.56)
Placebo 60.73 (10.97) 54.93 (11.13) 55.40 (11.65)
QIDS-SR
All   Sirolimus 14.48 (3.97) 11.27 (5.03) 11.56 (5.13)
Placebo 13.79 (4.45) 11.75 (3.75) 11.29 (4.32)
Vietnam   Sirolimus 14.38 (3.99) 14.50 (3.54) 13.25 (5.41)
Placebo 13.89 (4.75) 11.67 (3.96) 10.56 (4.82)
Post-Vietnam   Sirolimus 14.53 (4.07) 9.83 (4.99) 10.84 (4.98)
Placebo 13.73 (4.43) 11.80 (3.76) 11.73 (4.11)
at=2.32; df=31; Cohen’s d=0.81; P=.027.
bt=2.43; df=31; Cohen’s d=0.84;, P=.021.
ct=2.25; df=31; Cohen’s d=0.52; P=.032.
CAPS: Clinician-Administered PTSD Scale; PCL: PTSD Checklist; QIDS-SR: Quick Inventory of Depressive Symptomatology (Self-Report).

  DISCUSSION

The primary aim of this translational pilot study was to determine whether traumatic memory reactivation paired with a single dose of sirolimus would: 1) decrease the frequency and intensity of PTSD symptoms 1 month and 3 months posttreatment compared with participants receiving placebo, and 2) decrease the intensity of the trauma-related physiologic responses to trauma memories.

No significant treatment-group differences were found for any of the symptom or physiologic measures when the entire veteran sample was examined, ie, veterans with combat trauma ranging from 3 to 40 years ago. In analyses with the post-Vietnam subsample only, the sirolimus-treated participants reported significantly fewer and less intense PTSD symptoms (PCL and CAPS total score and group D symptom score) at 1 month posttreatment. These effects did not persist at 3 months.

Although initial results appear promising, this exploratory pilot study has several limitations. The timing of the medication may not have been optimized, because peak levels of sirolimus are found 1 hour post administration. Because the procedure for reactivation of the trauma memory (writing the narrative) lasted 45 minutes on average, the peak sirolimus concentration in the bloodstream—generally requiring ≥1 hour21—may not have been reached during the procedure. The relatively small sample size limited statistical power, potentially reducing detectable differences between the treatment groups. The convenience nature of the sample limits potential generalizability of these findings to veterans with PTSD in treatment settings. Corrections for multiple comparisons such as Bonferroni were not made because of the small sample size and the pilot nature of the study.

Despite these limitations, findings from the post-Vietnam veteran subgroup showed statistically significant improvements in PTSD symptoms at 1 month post treatment. It may be that only the less chronic trauma memories of the younger post-Vietnam veteran cohorts are amenable to modification by sirolimus. Consistent with these findings, the preclinical literature on traumatic memory reconsolidation suggests that more recent memories are more amenable to interference with reconsolidation, and older traumatic memories are much less susceptible to pharmacologic blockade of reconsolidation.22,23

  CONCLUSIONS

This exploratory pilot study demonstrated the safety and feasibility of using sirolimus combined with reactivation of a traumatic combat-related memory as a potential treatment for PTSD in male combat veterans. No adverse events occurred from administration of the study medication or from the use of the trauma script. The results suggested potential positive effects from a single sirolimus administration. These results suggest that further investigation may be warranted into the potential for this medication to ameliorate military-related psychological trauma through interference with the reconsolidation of fear memories. Future research may benefit by focusing on veterans of more recent eras whose traumatic memories may be less entrenched and more amenable to change. Because the effects of sirolimus in this study appeared to diminish by 3 months after a single dose, future investigation is warranted to explore whether repeated pairings (eg, 4 to 6 sessions) of sirolimus and trauma reactivation might be more effective than a single administration in reducing PTSD symptoms over time.

DISCLOSURES: This manuscript was supported by a grant awarded to Drs. Surís and Powell from the University of Texas Southwestern Medical Center Multidisciplinary Clinical and Translational Pilot and Collaborative Study Initiative Award and the Blue Gator Foundation. Supported in part by grant UL1 RR024982 from the Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health (NIH). Supplemental funding was provided by the Dallas VA Research Corporation.

Dr. Surís also receives grant support from the US Department of Defense and the VA Rehabilitation Research and Development Service. Dr. Smith reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Powell is a consultant to the Autism Speak Foundation and the NIH. Dr. North receives grant or research support from the American Psychiatric Association, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, the Orthopaedic Trauma Association, and the US Department of Veterans Affairs; is a consultant to the Tarrant County (TX) Department of Health and the University of Oklahoma Health Sciences Center; and is a speaker for the Pueblo City/County (CO) Department of Health.

Clinical trial# NCT01449955, at http://clinicaltrials.gov/

ACKNOWLEDGEMENTS: The authors wish to thank Scott Orr, PhD, for his ongoing role as psychophysiology consultant and for his editorial contribution to this manuscript. We would also like to recognize Sharjeel Farooqui, Anupma Dhingra, Christina Bass, Elizabeth Morris, and Sharon Marcus for their involvement in recruiting participants and in collecting and entering data.

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CORRESPONDENCE: Alina Surís, PhD, ABPP, VA North Texas Health Care System, Mental Health (116A), 4500 S. Lancaster Road, Dallas, TX 75216 USA, E-MAIL: Alina.Suris@va.gov