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1.  Tachikawa project for prevention of posttraumatic stress disorder with polyunsaturated fatty acid (TPOP): study protocol for a randomized controlled trial 
BMC Psychiatry  2013;13:8.
Preclinical and clinical studies suggest that supplementation with omega-3 fatty acids after trauma might reduce subsequent posttraumatic stress disorder (PTSD). To date, we have shown in an open trial that PTSD symptoms in critically injured patients can be reduced by taking omega-3 fatty acids, hypothesized to stimulate hippocampal neurogenesis. The primary aim of the present randomized controlled trial is to examine the efficacy of omega-3 fatty acid supplementation in the secondary prevention of PTSD following accidental injury, as compared with placebo. This paper describes the rationale and protocol of this trial.
The Tachikawa Project for Prevention of Posttraumatic Stress Disorder with Polyunsaturated Fatty Acid (TPOP) is a double-blinded, parallel group, randomized controlled trial to assess whether omega-3 fatty acid supplementation can prevent PTSD symptoms among accident-injured patients consecutively admitted to an intensive care unit. We plan to recruit accident-injured patients and follow them prospectively for 12 weeks. Enrolled patients will be randomized to either the omega-3 fatty acid supplement group (1,470 mg docosahexaenoic acid and 147 mg eicosapentaenoic acid daily) or placebo group. Primary outcome is score on the Clinician-Administered PTSD Scale (CAPS). We will need to randomize 140 injured patients to have 90% power to detect a 10-point difference in mean CAPS scores with omega-3 fatty acid supplementation compared with placebo. Secondary measures are diagnosis of PTSD and major depressive disorder, depressive symptoms, physiologic response in the experiment using script-driven imagery and acoustic stimulation, serum brain-derived neurotrophic factor, health-related quality of life, resilience, and aggression. Analyses will be by intent to treat. The trial was initiated on December 13 2008, with 104 subjects randomized by November 30 2012.
This study promises to be the first trial to provide a novel prevention strategy for PTSD among traumatized people.
Trial registration Identifier NCT00671099
PMCID: PMC3598223  PMID: 23289548
Fish oil; Omega-3 fatty acid; Docosahexaenoic acid; Eicosapentaenoic acid; Posttraumatic stress disorder; Accidental injury; Prevention
2.  Potential impact of propofol immediately after motor vehicle accident on later symptoms of posttraumatic stress disorder at 6-month follow up: a retrospective cohort study 
Critical Care  2012;16(5):R196.
Critically injured patients are at risk of developing posttraumatic stress disorder (PTSD). Propofol was recently reported to enhance fear memory consolidation retrospectively. Thus, we investigated here whether administration of propofol within 72 h of a motor vehicle accident (MVA) affects the subsequent development of PTSD symptoms.
We examined data obtained from a prospective cohort study of MVA-related injured patients, admitted to the intensive care unit of a general hospital. We investigated the effect of propofol administration within 72 h of MVA on outcome. Primary outcome was diagnosis of full or partial PTSD as determined by the Clinician-Administered PTSD Scale (CAPS) at 6 months. Secondary outcomes were diagnosis of full or partial PTSD at 1 month and CAPS score indicating PTSD at 1 and 6 months. Multivariate analysis was conducted adjusting for being female, age, injury severity score (ISS), and administration of ketamine or midazolam within 72 h of MVA.
Among 300 patients recruited (mean ISS, 8.0; median Glasgow Coma Scale (GCS) score, 15.0; age, 18 to 69 years), propofol administration showed a higher risk for full or partial PTSD as determined by CAPS at 6 months (odds ratio = 6.13, 95% confidence interval (CI): 1.57 to 23.85, P = 0.009) and at 1 month (odds ratio = 1.31, 95% CI: 0.41 to 4.23, P = 0.647) in the multivariate logistic regression. Multivariate regression analysis showed a trend toward adverse effects of propofol on PTSD symptom development at 6 months after MVA (β = 4.08, 95% CI: -0.49 to 8.64, P = 0.080), but not at 1 month after MVA (β = -0.42, 95% CI: -6.34 to 5.51, P = 0.890).
These findings suggest that using propofol in the acute phase after MVA might be associated with the development of PTSD symptoms 6 months later. However, since the design of this study was retrospective, these findings should be interpreted cautiously and further study is warranted.
PMCID: PMC3682298  PMID: 23075426
3.  Attenuating posttraumatic distress with omega-3 polyunsaturated fatty acids among disaster medical assistance team members after the Great East Japan Earthquake: The APOP randomized controlled trial 
BMC Psychiatry  2011;11:132.
On March 11, 2011, a magnitude 9.0 earthquake, the most powerful ever recorded in Japan, and a massive tsunami struck off the coast of the Sanriku region. A Disaster Medical Assistance Team, a mobile medical team with specialized training that is deployed during the acute phase of a disaster, was dispatched to areas with large-scale destruction and multiple injured and sick casualties. Previous studies have reported critical incident stress (i.e. posttraumatic stress disorder symptoms and depressive symptoms) among rescue workers as well as the need for screening and prevention for posttraumatic stress disorder. So far we have shown in an open trial that posttraumatic stress disorder symptoms in critically injured patients can be reduced by taking omega-3 fatty acids intended to stimulate hippocampal neurogenesis.
This study is designed to determine the effectiveness of attenuating posttraumatic distress with omega-3 polyunsaturated fatty acids among Disaster Medical Assistance Team members after the Great East Japan Earthquake, and is named the APOP randomized controlled trial which is currently ongoing. First, we will provide psycho-education on posttraumatic distress, which is common in responders to the Disaster Medical Assistance Team members deployed to the disaster area. Second, observational research will be conducted to evaluate critical incident stress following the completion of medical activities. Third, team members who provide consent to participate in the intervention research will be randomly divided into a group given an omega-3 fatty acid supplement and a group not given the supplements. Outcome will be evaluated at 12 weeks after the supplements are shipped to the team members.
Measures that address critical incident stress in disaster responders are important, but there is no substantial evidence that links such measures with prevention of posttraumatic stress disorder. Thus, any confirmation through this study that the intake of omega-3 fatty acid supplements serves as a simple preventative measure for critical incident stress will be of great significance.
Trial registration
UMIN Clinical Trials Registry, UMIN000005367
PMCID: PMC3167761  PMID: 21846343
4.  Prevalence rate, predictors and long-term course of probable posttraumatic stress disorder after major trauma: a prospective cohort study 
BMC Psychiatry  2012;12:236.
Among trauma patients relatively high prevalence rates of posttraumatic stress disorder (PTSD) have been found. To identify opportunities for prevention and early treatment, predictors and course of PTSD need to be investigated. Long-term follow-up studies of injury patients may help gain more insight into the course of PTSD and subgroups at risk for PTSD. The aim of our long-term prospective cohort study was to assess the prevalence rate and predictors, including pre-hospital trauma care (assistance of physician staffed Emergency Medical Services (EMS) at the scene of the accident), of probable PTSD in a sample of major trauma patients at one and two years after injury. The second aim was to assess the long-term course of probable PTSD following injury.
A prospective cohort study was conducted of 332 major trauma patients with an Injury Severity Score (ISS) of 16 or higher. We used data from the hospital trauma registry and self-assessment surveys that included the Impact of Event Scale (IES) to measure probable PTSD symptoms. An IES-score of 35 or higher was used as indication for the presence of probable PTSD.
One year after injury measurements of 226 major trauma patients were obtained (response rate 68%). Of these patients 23% had an IES-score of 35 or higher, indicating probable PTSD. At two years after trauma the prevalence rate of probable PTSD was 20%. Female gender and co-morbid disease were strong predictors of probable PTSD one year following injury, whereas minor to moderate head injury and injury of the extremities (AIS less than 3) were strong predictors of this disorder at two year follow-up. Of the patients with probable PTSD at one year follow-up 79% had persistent PTSD symptoms a year later.
Up to two years after injury probable PTSD is highly prevalent in a population of patients with major trauma. The majority of patients suffered from prolonged effects of PTSD, underlining the importance of prevention, early detection, and treatment of injury-related PTSD.
PMCID: PMC3558452  PMID: 23270522
Major trauma; Posttraumatic stress disorder; Follow-up study
5.  Trauma Exposure and Posttraumatic Stress Disorder in a National Sample of Adolescents 
Although exposure to potentially traumatic experiences (PTEs) is common among US youths, information on posttraumatic stress disorder (PTSD) risk associated with PTEs is limited. We estimate lifetime prevalence of exposure to PTEs and PTSD, PTE-specific risk of PTSD, and associations of sociodemographics and temporally-prior DSM-IV disorders with PTE exposure, PTSD given exposure, and PTSD recovery among US adolescents.
Data were drawn from 6,483 adolescent–parent pairs in the National Comorbidity Survey Replication Adolescent Supplement (NCS-A), a national survey of adolescents aged 13–17. Lifetime exposure to interpersonal violence, accidents/injuries, network/witnessing, and other PTEs was assessed along with DSM-IV PTSD and other distress, fear, behavior, and substance disorders.
A majority (61.8%) of adolescents experienced a lifetime PTE. Lifetime prevalence of DSM-IV PTSD was 4.7% and was significantly higher among females (7.3%) than males (2.2%). Exposure to PTEs, particularly interpersonal violence, was highest among adolescents not living with both biological parents and with pre-existing behavior disorders. Conditional probability of PTSD was highest for PTEs involving interpersonal violence. Predictors of PTSD among PTE-exposed adolescents included female gender, prior PTE exposure, and pre-existing fear and distress disorders. One-third (33.0%) of adolescents with lifetime PTSD continued to meet criteria within 30 days of interview. Poverty, U.S. nativity, bipolar disorder, and PTE exposure occurring after the focal trauma predicted nonrecovery.
Interventions designed to prevent PTSD in PTE-exposed youths should be targeted at victims of interpersonal violence with pre-existing fear and distress disorders, whereas interventions designed to reduce PTSD chronicity should attempt to prevent secondary PTE exposure.
PMCID: PMC3724231  PMID: 23880492
adolescent; posttraumatic stress disorder (PTSD); trauma; violence
6.  Re-examination of the Controversial Coexistence of Traumatic Brain Injury and Posttraumatic Stress Disorder: Misdiagnosis and Self-Report Measures 
Psychological Injury and Law  2010;3(1):63-76.
The coexistence of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) remains a controversial issue in the literature. To address this controversy, we focused primarily on the civilian-related literature of TBI and PTSD. Some investigators have argued that individuals who had been rendered unconscious or suffered amnesia due to a TBI are unable to develop PTSD because they would be unable to consciously experience the symptoms of fear, helplessness, and horror associated with the development of PTSD. Other investigators have reported that individuals who sustain TBI, regardless of its severity, can develop PTSD even in the context of prolonged unconsciousness. A careful review of the methodologies employed in these studies reveals that investigators who relied on clinical interviews of TBI patients to diagnose PTSD found little or no evidence of PTSD. In contrast, investigators who relied on PTSD questionnaires to diagnose PTSD found considerable evidence of PTSD. Further analysis revealed that many of the TBI patients who were initially diagnosed with PTSD according to self-report questionnaires did not meet the diagnostic criteria for PTSD upon completion of a clinical interview. In particular, patients with severe TBI were often misdiagnosed with PTSD. A number of investigators found that many of the severe TBI patients failed to follow the questionnaire instructions and erroneously endorsed PTSD symptoms because of their cognitive difficulties. Because PTSD questionnaires are not designed to discriminate between PTSD and TBI symptoms or determine whether a patient's responses are accurate or exaggerated, studies that rely on self-report questionnaires to evaluate PTSD in TBI patients are at risk of misdiagnosing PTSD. Further research should evaluate the degree to which misdiagnosis of PTSD occurs in individuals who have sustained mild TBI.
PMCID: PMC2948674  PMID: 20927197
Posttraumatic stress disorder; Traumatic brain injury
7.  Protocol for a randomised controlled trial of risk screening and early intervention comparing child- and family-focused cognitive-behavioural therapy for PTSD in children following accidental injury 
BMC Psychiatry  2010;10:92.
Accidental injury represents the most common type of traumatic event to which a child or adolescent may be exposed, with a significant number of these children going on to experience posttraumatic stress disorder (PTSD). However, very little research has examined potential interventions for the treatment of PTSD in these children. The present trial aims to evaluate and compare child- and family-focused versions of a cognitive-behavioural early intervention for PTSD following accidental injury.
The principal clinical question under investigation is the efficacy of an early, trauma-focused cognitive-behavioural intervention for the treatment of PTSD in children following accidental injury. Specifically, we compare the efficacy of two active treatments (child-focused and family-focused CBT) and a waitlist control (no therapy) to determine which is associated with greater reductions in psychological and health-related outcome measures over time. The primary outcome will be a reduction in trauma symptoms on a diagnostic interview in the active treatments compared to the waitlist control and greater reductions in the family-compared to the child-focused condition. In doing so, this project will also trial a method of stepped screening and assessment to determine those children requiring early intervention for PTSD following accidental injury.
The present trial will be one of the first controlled trials to examine a trauma-focused CBT, early intervention for children experiencing PTSD following accidental injury (as opposed to other types of traumatic events) and the first within a stepped care approach. In addition, it will provide the first evidence comparing the efficacy of child and family-focused interventions for this target group. Given the significant number of children and adolescents exposed to accidental injury, the successful implementation of this protocol has considerable implications. If efficacious, this early intervention will assist in reducing symptoms of traumatic stress as well as preventing chronic disorder and disability in children experiencing acute PTSD following accidental injury.
Trial Registration ISRCTN79049138
PMCID: PMC2998467  PMID: 21078196
8.  Sleep disturbances and PTSD: a perpetual circle? 
European Journal of Psychotraumatology  2012;3:10.3402/ejpt.v3i0.19142.
Sleep facilitates the consolidation of fear extinction memory. Nightmares and insomnia are hallmark symptoms of posttraumatic stress disorder (PTSD), possibly interfering with fear extinction and compromising recovery. A perpetual circle may develop when sleep disturbances increase the risk for PTSD and vice versa. To date, therapeutic options for alleviating sleep disturbances in PTSD are limited.
We conducted three studies to examine the relationship between sleep and posttraumatic symptoms: (1) a prospective longitudinal cohort study examining the impact of pre-deployment insomnia symptoms and nightmares on the development of PTSD; (2) a cross-sectional study examining subjective sleep measures, polysomnography, endocrinological parameters, and memory in veterans with PTSD, veterans without PTSD, and healthy controls (HCs); (3) a randomized controlled trial (RCT) (n=14) comparing the effect of prazosin and placebo on sleep disturbances in veterans with PTSD. In addition to these studies, we systematically reviewed the literature on treatment options for sleep disturbances in PTSD.
Pre-deployment nightmares predicted PTSD symptoms at 6 months post-deployment; however, insomnia symptoms did not. Furthermore, in patients with PTSD, a correlation between the apnea index and PTSD severity was observed, while obstructive sleep apnea syndrome was not more prevalent. We observed a significant increase in awakenings during sleep in patients with PTSD, which were positively correlated with adrenocorticotropic hormone (ACTH) levels, negatively correlated with growth hormone (GH) secretion, and the subjective perception of sleep depth. Also, heart rate was significantly increased in PTSD patients. Interestingly, plasma levels of GH during the night were decreased in PTSD. Furthermore, GH secretion and awakenings were independent predictors for delayed recall, which was lower in PTSD. In our RCT, prazosin was not associated with improvement of any subjective and objective sleep parameters. Only a few RCTs have been published. They show promising results for atypical antipsychotics and prazosin, the latter especially on nightmare reduction.
Disturbed sleep due to nightmares increases the risk for PTSD. PTSD in turn leads to increased sleep fragmentation, decreased GH secretion, and frequent nightmares, which may again compromise fear extinction, synaptic plasticity, and recovery. This suggests that disturbed sleep is a precipitating and perpetuating factor in PTSD symptomatology, creating a perpetual circle. This dissertation suggests that activity of the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system (SNS) is involved in disturbed sleep in patients with PTSD.
PMCID: PMC3464455  PMID: 23050070
PTSD; sleep; nightmares; polysomnography; cortisol; growth hormone; memory; noradrenalin
Depression and anxiety  2012;29(10):833-842.
The high prevalence of trauma exposure and subsequent negative consequences for both survivors and society as a whole emphasize the need for secondary prevention of posttraumatic stress disorder. However, clinicians and relief workers remain limited in their ability to intervene effectively in the aftermath of trauma and alleviate traumatic stress reactions that can lead to chronic PTSD. The scientific literature on early intervention for PTSD is reviewed, including early studies on psychological debriefing, pharmacological, and psychosocial interventions aimed at preventing chronic PTSD. Studies on fear extinction and memory consolidation are discussed in relation to PTSD prevention and the potential importance of immediate versus delayed intervention approaches and genetic predictors are briefly reviewed. Preliminary results from a modified prolonged exposure intervention applied within hours of trauma exposure in an emergency room setting are discussed, along with considerations related to intervention reach and overall population impact. Suggestions for future research are included. Prevention of PTSD, although currently not yet a reality, remains an exciting and hopeful possibility with current research approaches translating work from the laboratory to the clinic.
PMCID: PMC3665083  PMID: 22941845
secondary prevention; early intervention; PTSD; ASD
10.  Heart rate responses to standardized trauma-related pictures in acute posttraumatic stress disorder 
Physiological responses to trauma reminders are one of the core symptoms of posttraumatic stress disorder (PTSD). Nevertheless, screening measures for PTSD largely rely on symptom self-reports. It has been suggested that psychophysiological assessments may be useful in identifying trauma survivors with PTSD (Orr and Roth, 2000). This study investigated whether heart rate (HR) responses to standardized trauma-related pictures distinguish between trauma survivors with and without acute PTSD.
Survivors of motor vehicle accidents or physical assaults (N = 162) watched standardized trauma-related, generally threatening and neutral pictures at 1 month post-trauma while their ECG was recorded. At 1 and 6 months, structured clinical interviews assessed PTSD diagnoses. Participants completed self-report measures of PTSD severity and depression, peritraumatic responses, coping behaviors and appraisals.
Trauma survivors with acute PTSD showed greater HR responses to trauma-related pictures than those without PTSD, as indicated by a less pronounced mean deceleration, greater peak responses, and a greater proportion showing HR acceleration of greater than 1 beat per minute. There were no group differences in HR responses to generally threatening or neutral pictures. HR responses to trauma-related pictures contributed to the prediction of PTSD diagnosis over and above what could be predicted from self-reports of PTSD and depression. HR responses to trauma-related pictures were related to fear and data-driven processing during the trauma, safety behaviors, suppression of trauma memories, and overgeneralized appraisals of danger.
The results suggest that HR responses to standardized trauma-related pictures may help identify a subgroup of patients with acute PTSD who show generalized fear responses to trauma reminders. The early generalization of triggers of reexperiencing symptoms observed in this study is consistent with associative learning and cognitive models of PTSD.
PMCID: PMC2965012  PMID: 20450940
Posttraumatic stress disorder; Depression; Heart rate; Associative learning; Anxiety; Cognitive models; Stimulus generalization
11.  Structural and functional plasticity of the human brain in posttraumatic stress disorder 
Progress in brain research  2008;167:171-186.
Posttraumatic stress disorder (PTSD) is associated with long-term changes in neurobiology. Brain areas involved in the stress response include the medial prefrontal cortex, hippocampus, and amygdala. Neurohormonal systems that act on the brain areas to modulate PTSD symptoms and memory include glucocorticoids and norepinephrine. Dysfunction of these brain areas is responsible for the symptoms of PTSD. Brain imaging studies show that PTSD patients have increased amygdala reactivity during fear acquisition. Other studies show smaller hippocampal volume. A failure of medial prefrontal/anterior cingulate activation with re-experiencing of the trauma is hypothesized to represent a neural correlate of the failure of extinction seen in PTSD. The brain has the capacity for plasticity in the aftermath of traumatic stress. Antidepressant treatments and changes in environment can reverse the effects of stress on hippocampal neurogenesis, and humans with PTSD showed increased hippocampal volume with both paroxetine and phenytoin.
PMCID: PMC3226705  PMID: 18037014
PET; depression; cortisol; glucocorticoids; stress; PTSD
12.  Feasibility of Identifying Eligible Trauma Patients for Posttraumatic Stress Disorder Intervention 
This research report examines the feasibility of identifying eligible trauma patients for a study providing an early therapeutic intervention for the prevention of posttraumatic stress disorder (PTSD), and identifies reasons around participation.
This prospective observational study used a convenience sample of acute trauma victims presenting to a university-affiliated Level One trauma center in a large southeastern city. Patients eligible to participate in the early intervention study were adults (18– 65) who experienced a traumatic event within 72 hours of presentation, feared that they might be killed or seriously injured during the event, and were able to return for follow-up appointments. Patients were excluded if they were non-English speaking; experienced a loss of consciousness greater than five minutes; had a history of a serious mental illness or were currently suicidal; or endorsed current substance dependence. Descriptive statistics were conducted to determine differences in ineligible, eligible, and consenting trauma patients who enrolled in the intervention study.
Over a six-month period, n =1961 patients presented for treatment of a traumatic injury during study hours. Results showed that eligible patients were significantly younger than ineligible patients. Survivors of assaults (physical and sexual), younger patients, and women were generally more likely to participate in a study offering a psychological intervention in the immediate aftermath of a traumatic event.
Fourteen percent of trauma patients were eligible and entered a study offering an early psychological intervention for the prevention of PTSD. Trauma type, age and gender may play a role in determining preference for receiving psychological services immediately after experiencing a traumatic event.
PMCID: PMC2941366  PMID: 20882149
13.  PTSD and Gene Variants: New Pathways and New Thinking 
Neuropharmacology  2011;62(2):628-637.
Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated – the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenegic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions.
PMCID: PMC3136568  PMID: 21356219
14.  Posttraumatic stress disorder among earthquake survivors of the Wenchuan area (Sichuan, China) 
European Journal of Psychotraumatology  2014;5:10.3402/ejpt.v5.26531.
On May 12, 2008, an earthquake with a power of 8.0 M on the Richter scale occurred in the Wenchuan County of Sichuan Province in southwest China, which was unprecedented in magnitude and aftermath. Approximately 70,000 people were killed and nearly 20,000 went missing. The earthquake caused a wide number of mental and physical health outcomes among survivors, and posttraumatic stress disorder (PTSD) was one of the most commonly studied.
We conducted a systematic overview to assess research achievements about PTSD in the past 6 years after the Wenchuan earthquake, including symptoms and risk factors about PTSD among Wenchuan earthquake survivors, as well as research developments in genetics, molecular biology, and treatment of PTSD.
The large body of research conducted after the Wenchuan earthquake suggests that the burden of PTSD among persons with high exposure was substantial. Adolescents and adults were among the most studied populations with high prevalence rates. Phytotherapy with Chinese herbs as well as acupuncture were rarely studied as of yet, although published data indicated promising therapy effects. Genome-wide microarray technologies are widely used in experimental mice and rat models to study PTSD mechanisms as well as in patients suffering from PTSD and other psychosomatic disorders to search for novel biomarkers and to monitor the effectiveness of treatment interventions.
Using genomic and transcriptomic technologies, our future research will focus on the efficacy and safety of Chinese medicine to find potential interventions and effective treatments of PTSD.
PMCID: PMC4265177  PMID: 25511735
PTSD; earthquake; biomarker; phytotherapy; intervention
15.  How the Neurocircuitry and Genetics of Fear Inhibition May Inform Our Understanding of PTSD 
The American journal of psychiatry  2010;167(6):648-662.
Exposure to traumatic events that produce extreme fear and horror is all too common in both military and civilian populations, but not all individuals develop posttraumatic stress disorder (PTSD) as a result of the exposure. What mediates risk and resilience in the development of PTSD and other stress-related psychopathology is of paramount importance to our further understanding of trauma-related psychopathology as well as the development of new treatment approaches. Biological factors, such as genotype and neurobiology, interact with environmental factors, such as childhood background and trauma load, to affect vulnerability and resilience in the aftermath of trauma exposure. One of the core symptoms of PTSD is the inability to control fear, which has led some investigators and clinicians to conceptualize PTSD as a disorder of fear or, more importantly, its inhibition. This review focuses on translational methods that have been used to examine fear conditioning and inhibition of fear in PTSD and summarizes genetic and neurobiological factors related to fear inhibition. The authors also discuss different pharmacological approaches that enhance fear inhibition and may improve treatment outcomes for patients with PTSD.
PMCID: PMC3603297  PMID: 20231322
16.  A Randomized Stepped Care Intervention Trial Targeting Posttraumatic Stress Disorder for Surgically Hospitalized Injury Survivors 
Annals of surgery  2013;257(3):390-399.
To test the effectiveness of a stepped care intervention model targeting posttraumatic stress disorder (PTSD) symptoms after injury.
Few investigations have evaluated interventions for injured patients with PTSD and related impairments that can be feasibly implemented in trauma surgical settings.
The investigation was a pragmatic effectiveness trial in which 207 acutely injured hospitalized trauma survivors were screened for high PTSD symptom levels and then randomized to a stepped combined, care management, psychopharmacology, and cognitive behavioral psychotherapy intervention (n = 104) or usual care control (n = 103) conditions. The symptoms of PTSD and functional limitations were reassessed at one-, three-, six-, nine-, and twelve-months after the index injury admission.
Regression analyses demonstrated that over the course of the year after injury, intervention patients had significantly reduced PTSD symptoms when compared to controls (group by time effect, CAPS, F(2, 185) = 5.50, P < 0.01; PCL-C, F(4, 185) = 5.45, P < 0.001). Clinically and statistically significant PTSD treatment effects were observed at the six-, nine-, and twelve-month post-injury assessments. Over the course of the year after injury, intervention patients also demonstrated significant improvements in physical function (MOS SF-36 PCS main effect, F(1, 172) = 9.87, P < 0.01).
Stepped care interventions can reduce PTSD symptoms and improve functioning over the course of the year after surgical injury hospitalization. Orchestrated investigative and policy efforts could systematically introduce and evaluate screening and intervention procedures for PTSD at United States trauma centers. (Trial Registration: identifier: NCT00270959)
PMCID: PMC3582367  PMID: 23222034
17.  Factors Identifying Risk for Psychological Distress in the Civilian Trauma Population 
The emergency department (ED) is a valuable setting to initiate intervention in order to prevent future complications following traumatic injury. Posttraumatic stress disorder (PTSD) occurs in 10% to 40% of patients after single-incident civilian trauma. Prior research suggests young age is associated with increased risk. We hypothesized that other factors correlated with age may be responsible. The aim of this study was to determine if factors identifiable in the ED can better explain the relationship between younger age and PTSD, therefore more specifically identifying those at risk for long-term distress.
The influence of age on PTSD severity scores was isolated using data from an established screening program for all admitted trauma patients at a Level I trauma center. The PTSD Checklist, Civilian (PCLC) was administered prospectively to 527 adult trauma patients in order to measure PTSD symptom severity immediately post-trauma. Patient and trauma characteristics were then reviewed using medical records. Hierarchical linear regression modeled and evaluated the independent association of age with PTSD symptom severity, and explored additional variables as better predictors of risk.
PTSD symptom severity was associated individually with younger age, ethnic minority status, assaultive trauma, unemployment, low household income, and being unmarried, but not with sex, Injury Severity Score, or Glasgow Coma Scale score at the scene. Multivariate analysis demonstrated assaultive trauma and lower socioeconomic status (SES) were best associated with greater PCLC scores, accounting for 9.3% of the variance. Age did not account for additional variance.
Although young age is associated with increased PTSD symptom severity scores, characteristics associated with young age, specifically assaultive trauma and low SES, account for this risk. Young age is not an independent risk factor for PTSD. Psychological assessment in the ED can be targeted towards assaultive trauma patients, especially those of low SES, to establish early intervention and hopefully prevent the development of PTSD.
PMCID: PMC3220731  PMID: 22044521
18.  Internet-Based Early Intervention to Prevent Posttraumatic Stress Disorder in Injury Patients: Randomized Controlled Trial 
Posttraumatic stress disorder (PTSD) develops in 10-20% of injury patients. We developed a novel, self-guided Internet-based intervention (called Trauma TIPS) based on techniques from cognitive behavioral therapy (CBT) to prevent the onset of PTSD symptoms.
To determine whether Trauma TIPS is effective in preventing the onset of PTSD symptoms in injury patients.
Adult, level 1 trauma center patients were randomly assigned to receive the fully automated Trauma TIPS Internet intervention (n=151) or to receive no early intervention (n=149). Trauma TIPS consisted of psychoeducation, in vivo exposure, and stress management techniques. Both groups were free to use care as usual (nonprotocolized talks with hospital staff). PTSD symptom severity was assessed at 1, 3, 6, and 12 months post injury with a clinical interview (Clinician-Administered PTSD Scale) by blinded trained interviewers and self-report instrument (Impact of Event Scale—Revised). Secondary outcomes were acute anxiety and arousal (assessed online), self-reported depressive and anxiety symptoms (Hospital Anxiety and Depression Scale), and mental health care utilization. Intervention usage was documented.
The mean number of intervention logins was 1.7, SD 2.5, median 1, interquartile range (IQR) 1-2. Thirty-four patients in the intervention group did not log in (22.5%), 63 (41.7%) logged in once, and 54 (35.8%) logged in multiple times (mean 3.6, SD 3.5, median 3, IQR 2-4). On clinician-assessed and self-reported PTSD symptoms, both the intervention and control group showed a significant decrease over time (P<.001) without significant differences in trend. PTSD at 12 months was diagnosed in 4.7% of controls and 4.4% of intervention group patients. There were no group differences on anxiety or depressive symptoms over time. Post hoc analyses using latent growth mixture modeling showed a significant decrease in PTSD symptoms in a subgroup of patients with severe initial symptoms (n=20) (P<.001).
Our results do not support the efficacy of the Trauma TIPS Internet-based early intervention in the prevention of PTSD symptoms for an unselected population of injury patients. Moreover, uptake was relatively low since one-fifth of individuals did not log in to the intervention. Future research should therefore focus on innovative strategies to increase intervention usage, for example, adding gameplay, embedding it in a blended care context, and targeting high-risk individuals who are more likely to benefit from the intervention.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 57754429; (Archived by WebCite at
PMCID: PMC3742408  PMID: 23942480
early intervention; prevention; Internet; posttraumatic stress disorder; cognitive behavior therapy
19.  Patient-reported outcomes in post-traumatic stress disorder Part II: Focus on pharmacological treatment 
Post-traumatic stress disorder (PTSD) may be associated with long-lasting psychological suffering, distressing psychosocial disability, markedly reduced health-related quality of life, and increased morbidity and mortality in a subgroup of individuals in the aftermath of serious traumatic events. Both etiopathogenesis and treatment modalities of PTSD are best conceptualized within a biopsychosotial model. Pharmacotherapy may lay claim to a major role in the multimodal treatment approaches. Here we outline two different pharmacotherapeutic trends that aim to modify the encoding, consolidation, and rehearsal of traumatic memory in order to reduce the risk of PTSD immediately after trauma exposure on the one hand, and that endeavor to treat the clinical state of PTSD on the other. The theoretical rationales of both pharmacological strategies are the complex neurobiological underpinnings that characterize traumatic memory organization and clinical PTSD. Meanwhile, promising data from randomized controlled trials have been obtained for both approaches. Empirical evidence may inform clinicians in their clinical efforts for this special group of patients. The efficacy of several classes of drugs that have been investigated within a context of research should be evaluated critically and still have to stand the test of effectiveness in daily clinical practice. From a patient perspective, empirical results may serve as a psychoeducative guideline to what pharmacotherapeutic approaches may realistically achieve, what their risks and benefits are, and what their limits are in contributing to reducing the often major chronic suffering caused by serious traumatic events. Ethical issues have to be considered, particularly in the context of pharmacological strategies projected to prevent PTSD in the aftermath of traumatic exposure.
PMCID: PMC4140515  PMID: 25152660
trauma; trauma memory; PTSD; pharmacotherapy; prevention
20.  Early Intervention May Prevent the Development of PTSD: A Randomized Pilot Civilian Study with Modified Prolonged Exposure 
Biological psychiatry  2012;72(11):957-963.
Posttraumatic stress disorder is a major public health concern with long term sequelae. There are no accepted interventions delivered in the immediate aftermath of trauma. This study tested an early intervention aimed at modifying the memory to prevent the development of PTSD prior to memory consolidation.
Patients (N=137) were randomly assigned to receive 3 sessions of an early intervention beginning in the emergency department (ED) compared to an assessment only control group. Posttraumatic stress reactions (PTSR) were assessed at 4 and 12 weeks post-injury and depression at baseline and week 4. The intervention consisted of modified prolonged exposure including imaginal exposure to the trauma memory, processing of traumatic material, and in vivo and imaginal exposure homework.
Patients were assessed an average of 11.79 hours post-trauma. Intervention participants reported significantly lower PTSR than the assessment group at 4 weeks post-injury, p < 0.01, and at 12 weeks post-injury, p < 0.05, and significantly lower depressive symptoms at Week 4 than the assessment group, p < 0.05. In a subgroup analysis the intervention was the most effective at reducing PTSD in rape victims at Week 4 (p=.004) and Week 12 (p=.05).
These findings suggest that the modified prolonged exposure intervention initiated within hours of the trauma in the ED is successful at reducing PTSR and depression symptoms one and three months after trauma exposure and is safe and feasible. This is the first behavioral intervention delivered immediately post-trauma that has been shown to be effective at reducing PTSR.
PMCID: PMC3467345  PMID: 22766415
early intervention; secondary prevention; PTSD; Acute Stress Disorder; prolonged exposure; memory consolidation
21.  Substance Use, Childhood Traumatic Experience and Post-traumatic Stress Disorder in an Urban Civilian Population 
Depression and anxiety  2010;27(12):1077-1086.
Exposure to traumatic experiences, especially those occurring in childhood, has been linked to substance use disorders (SUDs), including abuse and dependence. SUDs are also highly co-morbid with Posttraumatic Stress Disorder (PTSD) and other mood-related psychopathology. Most studies examining the relationship between PTSD and SUDs have examined veteran populations or patients in substance treatment programs. The present study further examines this relationship between childhood trauma, substance use, and PTSD in a sample of urban primary care patients.
There were 587 participants included in this study, all recruited from medical and OB/GYN clinic waiting rooms at Grady Memorial Hospital in Atlanta, GA. Data were collected through both screening interviews as well as follow-up interviews.
In this highly traumatized population, high rates of lifetime dependence on various substances were found (39% alcohol, 34.1% cocaine, 6.2% heroin/opiates, 44.8% marijuana). The level of substance use, particularly cocaine, strongly correlated with levels of childhood physical, sexual, and emotional abuse as well as current PTSD symptoms. In particular, there was a significant additive effect of number of types of childhood trauma experienced with history of cocaine dependence in predicting current PTSD symptoms, and this effect was independent of exposure to adult trauma.
These data show strong links between childhood traumatization and SUDs, and their joint associations with PTSD outcome. They suggest that enhanced awareness of PTSD and substance abuse comorbidity in high-risk, impoverished populations is critical to understanding mechanisms of substance addiction as well as in improving prevention and treatment.
PMCID: PMC3051362  PMID: 21049532
African-American; Minority; Trauma; Childhood Maltreatment; Psychiatry; Alcohol; Cocaine; Opiate; Marijuana
22.  Substance use, childhood traumatic experience, and Posttraumatic Stress Disorder in an urban civilian population 
Depression and Anxiety  2010;27(12):1077-1086.
Objective: Exposure to traumatic experiences, especially those occurring in childhood, has been linked to substance use disorders (SUDs), including abuse and dependence. SUDs are also highly comorbid with Posttraumatic Stress Disorder (PTSD) and other mood-related psychopathology. Most studies examining the relationship between PTSD and SUDs have examined veteran populations or patients in substance treatment programs. The present study further examines this relationship between childhood trauma, substance use, and PTSD in a sample of urban primary care patients. Method: There were 587 participants included in this study, all recruited from medical and OB/GYN clinic waiting rooms at Grady Memorial Hospital in Atlanta, GA. Data were collected through both screening interviews as well as follow-up interviews. Results: In this highly traumatized population, high rates of lifetime dependence on various substances were found (39% alcohol, 34.1% cocaine, 6.2% heroin/opiates, and 44.8% marijuana). The level of substance use, particularly cocaine, strongly correlated with levels of childhood physical, sexual, and emotional abuse as well as current PTSD symptoms. In particular, there was a significant additive effect of number of types of childhood trauma experienced with history of cocaine dependence in predicting current PTSD symptoms, and this effect was independent of exposure to adult trauma. Conclusions: These data show strong links between childhood traumatization and SUDs, and their joint associations with PTSD outcome. They suggest that enhanced awareness of PTSD and substance abuse comorbidity in high-risk, impoverished populations is critical to understanding the mechanisms of substance addiction as well as in improving prevention and treatment. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc.
PMCID: PMC3051362  PMID: 21049532
African-American; minority; trauma; childhood maltreatment; psychiatry; alcohol; cocaine; opiate; Marijuana
23.  Amygdala-Dependent Fear Is Regulated by Oprl1 in Mice and Humans with PTSD 
Science translational medicine  2013;5(188):188ra73.
The amygdala-dependent molecular mechanisms driving the onset and persistence of posttraumatic stress disorder (PTSD) are poorly understood. Recent observational studies have suggested that opioid analgesia in the aftermath of trauma may decrease the development of PTSD. Using a mouse model of dysregulated fear, we found altered expression within the amygdala of the Oprl1 gene (opioid receptor–like 1), which encodes the amygdala nociceptin (NOP)/orphanin FQ receptor (NOP-R). Systemic and central amygdala infusion of SR-8993, a new highly selective NOP-R agonist, impaired fear memory consolidation. In humans, a single-nucleotide polymorphism (SNP) within OPRL1 is associated with a self-reported history of childhood trauma and PTSD symptoms (n = 1847) after a traumatic event. This SNP is also associated with physiological startle measures of fear discrimination and magnetic resonance imaging analysis of amygdala-insula functional connectivity. Together, these data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Further, our data suggest that activation of the Oprl1/NOP receptor may interfere with fear memory consolidation, with implications for prevention of PTSD after a traumatic event.
PMCID: PMC3732318  PMID: 23740899
24.  Substance Use Attenuates Physiological Responses Associated With PTSD among Individuals with Co-Morbid PTSD and SUDs 
Posttraumatic stress disorder (PTSD) is often conceptualized from a fear conditioning perspective given individuals with PTSD demonstrate a reduced ability to inhibit fear even under safe conditions as compared to those without PTSD. The self-medication hypothesis suggests that individuals with PTSD often develop substance use disorders (SUDs) as an attempt to mitigate trauma-related distressing emotions. This investigation examined this hypothesis in a sample 214 participants, of which 81 did not meet criteria for either PTSD or SUDs (No diagnosis Control group); 33 met criteria for lifetime PTSD, but not SUDs (PTSD only group); 54 met criteria for lifetime SUDs, but not PTSD (SUDs only group); and 46 met lifetime criteria for both disorders (PTSD+SUDs group). PTSD was assessed using the modified PTSD Symptoms Scale (mPSS), SUDs were assessed using the Structured Clinical Interview for DSM-IV-TR (SCID). The startle magnitude was assessed using electromyography (EMG) of the eyeblink muscle in response to an acoustic startle probe. Fear-potentiated startle (FPS) was analyzed by comparing startle magnitude at baseline to startle during a fear conditioned stimulus. Results showed that PTSD significantly increased startle responses. However, there was a significant effect of SUDs on fear-potentiated startle to the danger signal, in that those who met criteria for SUDs had reduced fear compared to those who did not. The individuals who had co-morbid PTSD and SUDs did not differ from the Control group. Findings indicate that SUDs may attenuate exaggerated fear responses associated with PTSD. Consistent with the self-medication hypothesis, results suggest that substance use may co-occur with PTSD because it reduces heightened fear load and may allow normalized function in traumatized individuals.
PMCID: PMC3882311  PMID: 24404418
PTSD; Substance abuse; Hyperarousal; Fear responding; Acoustic startle
25.  Posttraumatic stress symptoms and health-related quality of life: a two year follow up study of injury treated at the emergency department 
BMC Psychiatry  2012;12:1.
Among injury victims relatively high prevalence rates of posttraumatic stress disorder (PTSD) have been found. PTSD is associated with functional impairments and decreased health-related quality of life (HRQoL). Previous studies that addressed the latter were restricted to injuries at the higher end of the severity spectrum. This study examined the association between PTSD symptoms and health-related quality of life (HRQoL) in a comprehensive population of injury patients of all severity levels and external causes.
We conducted a self-assessment survey which included items regarding demographics of the patient, accident type, sustained injuries, EuroQol health classification system (EQ-5D) and Health Utilities Index (HUI) to measure functional outcome and HRQoL, and the Impact of Event Scale (IES) to measure PTSD symptoms. An IES-score of 35 or higher was used as indication for the presence of PTSD. The survey was completed by 1,781 injury patients two years after they were treated at the Emergency Department (ED), followed by either hospital admission or direct discharge to the home environment.
Symptoms indicative of PTSD were associated with more problems on all EQ-5D and HUI3 domains of functional outcome and a considerable utility loss in both hospitalized (0.23-0.24) and non-hospitalized (0.32-0.33) patients. Differences in reported problems between patients with IES scores higher or lower than 35 were largest for EQ-5D health domains pain/discomfort (82% versus 28%) and anxiety/depression (53% versus 11%) and HUI domains emotion (92% versus 33%) and pain (84% versus 38%). After adjusting for potential confounders, PTSD remained strongly associated with adverse HRQoL.
Among patients treated at an ED posttraumatic stress symptoms indicative of PTSD were associated with a considerable decrease in HRQoL in both hospitalized and non-hospitalized patients. PTSD symptoms may therefore raise a major barrier for full recovery of injury patients of even minor levels of severity.
PMCID: PMC3276433  PMID: 22230388
posttraumatic stress disorder; injury; functional outcome; quality of life

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