Association of 5-HTTLPR With Post-Traumatic Stress Disorder in US Service Members.

Objective: Post-traumatic stress disorder (PTSD) is a mental disorder that manifests after exposure to a stressful traumatic event, such as combat experience. Accumulated evidence indicates an important genetic influence in the development of PTSD. The serotonin transporter (5-HTT) gene has been identified as a candidate for PTSD and a polymorphism of the serotonin transporter-linked promoter region (5-HTTLPR) is associated with the disorder in the general population. However, whether it is associated with PTSD in active military service members has not been investigated. This study aimed to investigate the relationship between 5-HTTLPR and PTSD in service members. Methods: Leucocyte genomic DNA was extracted from service members, including those with PTSD (n = 134) or without PTSD (n = 639). The 5-HTTLPR polymorphism was detected by means of 2 stages of TaqMan fluorescent PCR assay. PTSD symptoms and symptom severity were assessed using the PTSD Checklist (PCL), a 17-item, DSM-based, self-report questionnaire with well-established validity and reliability. PTSD was determined based on endorsement of DSM-IV criteria and a PCL total score ≥ 44. Results: Significant differences in biallele distribution were observed between PTSD and controls (χ2 = 7.497, P = .024). The frequency of SS, SL, and LL genotypes in the PTSD group was 0.17, 0.56, and 0.27 respectively, compared to the frequencies of 0.27, 0.43, and 0.29 in non-PTSD controls. Carriers of the L allele had higher scores for reexperiencing and arousal symptoms on the PCL, compared to SS homozygote carriers (P < .05). The triallele genotypes showed no significant differences in distribution between the PTSD and control groups (P > .05) and no relationship with PTSD symptom severity. The interaction of triallelic genotypes of 5-HTTLPR and traumatic life events was associated with re-experiencing, avoidance, and arousal (P < .05 for all). Multiple regression analysis revealed significant correlations between both biallelic and triallelic genotypes of 5-HTTLPR, the interaction of the number of stressful lifetime events, and 5-HTTLPR genotypes with PCL total score (P < .001). Conclusion: Our findings suggested that 5-HTT might play a minor role in PTSD, and the interaction between 5-HTTLPR and the environment had effects on PCL score, complementing and emphasizing 5-HTT for PTSD, especially in the military population.

Perspectives of suicide loss survivors: Qualitative analysis of data from a psychological autopsy study of U.S. Army soldiers.

INTRODUCTION: Suicide loss survivors can provide information not otherwise available about the circumstances preceding a suicide. In this study, we analyzed interview data from suicide loss survivors collected as part of a psychological autopsy study of U.S. Army soldiers. METHODS: Next-of-kin (NOK) (n = 61) and Army supervisors (SUP) (n = 107) of suicide decedents (n = 135) who had died in the last 2-3 months answered open-ended questions about suicide risk factors, ideas for improving suicide prevention, and the impact of the suicide. Responses were coded using conventional content analysis methods to identify common themes. RESULTS: Many NOK (30%) and SUP (50%) did not observe any signs of risk preceding the soldier's suicide. The most common idea regarding suicide prevention from SUP was that the suicide was inevitable, whereas NOK were more likely to emphasize the importance of increasing mental health treatment and reducing stigma. Both NOK and SUP reported negative effects of the suicide, but SUP reported some positive effects (e.g., increased unit connectedness). CONCLUSIONS: Results underscore the challenges of using informants to identify soldiers at high risk of suicide, given many respondents did not observe any warning signs. Findings also highlight attitudinal barriers present in the military that, if targeted, may increase soldiers' help-seeking and willingness to disclose their risk.

Recent Stressful Experiences and Suicide Risk: Implications for Suicide Prevention and Intervention in U.S. Army Soldiers.

Objectives: To identify the extent to which the presence of recent stressful events are risk factors for suicide among active-duty soldiers as reported by informants. Methods: Next-of-kin (NOK) and supervisors (SUP) of active duty soldiers (n = 135) who died by suicide and two groups of living controls: propensity-matched (n = 128) and soldiers who reported suicidal ideation in the past year, but did not die (SI) (n = 108) provided data via structured interviews from the Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Multivariate logistic regression analyses were used to create a risk score for suicide. Results: The odds of suicide increased significantly for soldiers experiencing relationship problems, military punishment, and perceived failure or humiliation in the month prior to death. Suicide risk models with these risk factors predicted suicide death among those who reported SI in the past year (OR = 5.9, [95% CI = 1.5, 24.0] χ 2 = 6.24, p = 0.0125, AUC, 0.73 (0.7, 0.8) NOK) and (OR = 8.6, [95% CI = 1.4, 51.5] χ 2 = 5.49, p = 0.0191, AUC, 0.78 (0.7, 0.8); SUP) suggesting the combination of these recent stressors may contribute to the transition from ideation to action. Conclusions: Our findings suggest for the first time recent stressors distinguished suicide ideating controls from suicide decedents in the month prior to death as reported by informants. Implications for preventive intervention efforts for clinicians, supervisors and family members in identifying the transition from ideation to action are discussed.

Association of Traumatic Brain Injury Severity and Self-Reported Neuropsychiatric Symptoms in Wounded Military Service Members.

The impact of traumatic brain injury (TBI) severity and loss of consciousness (LOC) on the development of neuropsychiatric symptoms was studied in injured service members (SMs; n = 1278) evacuated from combat settings between 2003 and 2012. TBI diagnoses of mild TBI (mTBI) or moderate-to-severe TBI (MS-TBI) along with LOC status were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes and the Defense and Veterans Brain Injury Center Standard Surveillance Case Definition for TBI. Self-reported psychiatric symptoms were evaluated for post-traumatic stress disorder (PTSD) with the PTSD Checklist, Civilian Version for PTSD, the Patient Health Questionnaire-9 for major depressive disorder (MDD), and the Patient Health Questionnaire-15 for somatic symptom disorder (SSD) in two time periods post-injury: Assessment Period 1 (AP1, 0.0-2.5 months) and Assessment Period 2 (AP2, 3-12 months). mTBI, but not MS-TBI, was associated with increased neuropsychiatric symptoms: PTSD in AP1 and AP2; MDD in AP1; and SSD in AP2. A subgroup analysis of mTBI with and without LOC revealed that mTBI with LOC, but not mTBI without LOC, was associated with increased symptoms as compared to non-TBI: PTSD in AP1 and AP2; MDD in AP1; and SSD in AP1 and AP2. Moreover, mTBI with LOC was associated with increased MDD symptoms in AP2, and SSD symptoms in AP1 and AP2, compared to mTBI without LOC. These findings reinforce the need for the accurate characterization of TBI severity and a multi-disciplinary approach to address the devastating impacts of TBI in injured SMs.

Sex-related difference of association of mitochondrial DNA copy number with PTSD in U.S. service members.

Gender differences in the lifetime prevalence of post-traumatic stress disorder (PTSD) have been well described with rates reported as approximately 10%-12% in females and 5%-6% in males (Olff, 2017). This study examined whether the sex-related difference of mitochondrial DNA copy number (mtDNAcn), an emerging systemic index of mitochondrial biogenesis and function can serve as a potential biomarker for PTSD. Leukocyte mtDNAcn of service members with PTSD (male = 127, female = 24) or without PTSD (male = 621, female = 78) was assessed using a TaqMan assay. The results were validated by the absolute quantification of QX-200 droplet digital PCR (ddPCR). PTSD symptoms and symptom severity were assessed using the PTSD Checklist (PCL), a 17-item, DSM-based, self-report questionnaire with well-established validity and reliability. DSM-IV criteria and PTSD were determined by PCL total score. We found that mtDNAcn of female subjects with PTSD was significantly higher compared to either male or female non-PTSD controls or male subjects with PTSD (p < 0.05). There was no significant difference in mtDNAcn between males with PTSD and male/female controls without PTSD. Using in vitro cultured SH-SY5Y cells (human neuroblastoma), we demonstrated that estrogen (Estro) treatment significantly decreased mtDNAcn (P < 0.001) compared to the vehicle control. We also found that pre-treatment with either synthetic glucocorticoid dexamethasone (Dex) or Estro blocker tamoxifen (Tamox) attenuated the estrogen-induced decreases of mtDNAcn. Our data suggest that mtDNAcn may be gender-dependent in the Servicemembers with PTSD. Glucocorticoid and/or estrogen receptors may play a role in the regulation of mtDNAcn. The sex-related difference of mtDNAcn may serve as a PTSD biomarker for females.

Diverse therapeutic developments for post-traumatic stress disorder (PTSD) indicate common mechanisms of memory modulation.

Post-traumatic stress disorder (PTSD), characterized by abnormally persistent and distressing memories, is a chronic debilitating condition in need of new treatment options. Current treatment guidelines recommend psychotherapy as first line management with only two drugs, sertraline and paroxetine, approved by U.S. Food and Drug Administration (FDA) for treatment of PTSD. These drugs have limited efficacy as they only reduce symptoms related to depression and anxiety without producing permanent remission. PTSD remains a significant public health problem with high morbidity and mortality requiring major advances in therapeutics. Early evidence has emerged for the beneficial effects of psychedelics particularly in combination with psychotherapy for management of PTSD, including psilocybin, MDMA, LSD, cannabinoids, ayahuasca and ketamine. MDMA and psilocybin reduce barrier to therapy by increasing trust between therapist and patient, thus allowing for modification of trauma related memories. Furthermore, research into the memory reconsolidation mechanisms has allowed for identification of various pharmacological targets to disrupt abnormally persistent memories. A number of pre-clinical and clinical studies have investigated novel and re-purposed pharmacological agents to disrupt fear memory in PTSD. Novel therapeutic approaches like neuropeptide Y, oxytocin, cannabinoids and neuroactive steroids have also shown potential for PTSD treatment. Here, we focus on the role of fear memory in the pathophysiology of PTSD and propose that many of these new therapeutic strategies produce benefits through the effect on fear memory. Evaluation of recent research findings suggests that while a number of drugs have shown promising results in preclinical studies and pilot clinical trials, the evidence from large scale clinical trials would be needed for these drugs to be incorporated in clinical practice.

Effects of propranolol on the modification of trauma memory reconsolidation in PTSD patients: A systematic review and meta-analysis.

Post-traumatic stress disorder (PTSD) develops after an exposure to a life-threatening event and is characterized by intrusive memories. According to memory reconsolidation theory retrieval of memory under certain conditions leads to its labilization and subsequent re-storage which could be disrupted by drugs. Propranolol has been the most commonly investigated drug for memory reconsolidation therapy in clinical trials. Intervention with propranolol have shown mixed results in PTSD patients with some studies showing improvement in symptoms while other failing to replicate these findings. We conducted a systematic review and meta-analysis to determine the efficacy of trauma memory disruption by propranolol on PTSD symptoms and physiological responses in PTSD patients. 3224 publications were assessed for eligibility. Seven studies on effects of propranolol on PTSD symptoms and 3 studies on effects of propranolol on physiological responses were incorporated in the meta-analyses. Overall, results indicate that propranolol did not show a beneficial effect on PTSD symptoms (standardized mean difference: 1.29; 95% CI = -2.16 - 0.17). Similarly, propranolol did not influence skin conductance (standardized mean difference: 0.77; 95% CI = -1.85 - 0.31) or EMG response (standardized mean difference: 0.16; 95% CI = -0.65 - 0.33). However, propranolol significantly reduced heart rate after trauma memory recall compared to placebo (standardized mean difference: 0.67; 95% CI = -1.27 to -0.07). This study finds a lack of evidence for the efficacy of propranolol on traumatic memory disruption, in PTSD patients, to recommend its routine clinical use. However, a high level of heterogeneity, variation in propranolol dosage and inadequate sample sizes mean that these findings require cautious interpretation.

Somatic Symptom Severity, Not Injury Severity, Predicts Probable Posttraumatic Stress Disorder and Major Depressive Disorder in Wounded Service Members.

Although previous studies have reported an association between patient-reported somatic symptom severity and the development of posttraumatic stress disorder (PTSD) or major depressive disorder (MDD) in injured military service members (SMs), conclusions from other studies regarding the association between clinician-determined injury severity and PTSD or MDD remain unclear. The present study investigated whether somatic symptoms or injury severity predict the development of probable PTSD or MDD in wounded SMs medically evacuated from combat areas. Data including SM demographic characteristics, clinician-determined injury severity (i.e., Injury Severity Score [ISS] and Abbreviated Injury Scale [AIS] values), and self-report assessments of PTSD (PTSD Checklist-Civilian Version), MDD (Patient Health Questionnaire [PHQ]-9), and somatic symptoms (PHQ-15) were analyzed. A total of 2,217 SMs completed at least one self-assessment between 2003 and 2014, with 425 having completed assessments at each assessment period (AP), conducted 1-75 (AP1), 76-165 (AP2), and 166-255 (AP3) days postinjury. Between AP1 and AP3, the rates of probable PTSD and MDD increased from 3.0% to 11.7% and from 2.8% to 9.2%, respectively. Somatic symptom severity at AP1 predicted probable PTSD and MDD at all three APs, odds ratios (ORs) = 3.5-11.5; however, ISS values did not predict probable PTSD or MDD at any AP, ORs = 0.6-0.9. This suggests that the initial severity of self-reported somatic symptoms rather than clinician-determined injury severity predicts the development of probable PTSD and MDD in wounded SMs.

Hospitalization for physical injury may contribute to recovery of invisible war wounds: Response to Peterson's (2021) commentary on Soumoff et al. (2021).

Peterson's (2021) commentary on our recently published manuscript (Soumoff et al., 2021) suggests that our findings are an example of visible, physical injuries of war facilitating communication with others, which, in turn, fosters recovery from invisible war wounds. We agree that in the proper context, the retelling of one's traumatic story can be important for recovery from and, perhaps, even the prevention of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Participants in our study cohort differed from most others who experienced combat trauma in that while they were hospitalized, they experienced nearly daily visits from a behavioral health provider to address traumatic stress-related symptoms. It is likely that individuals who sustained more severe physical injury (i.e., higher Injury Severity Score [ISS] ratings) had longer hospital stays, received more support, and had more opportunities to retell their stories than those with less severe injuries, leading to decreases in PTSD and MDD symptoms. To note support of this supposition, in Table 5 of Soumoff et al. (2021), although not significant, the adjusted odds ratios (aORs) for PTSD and MDD were below 1 for service members with high (i.e., above 16) ISS ratings. The physical injury-related hospitalizations participants in our sample experienced fostered activities described by Peterson (2021) that likely contributed to the prevention and resolution of PTSD and MDD symptoms, benefits not received by most individuals who suffer only invisible wounds of war.

Mental Disorders, Gun Ownership, and Gun Carrying Among Soldiers After Leaving the Army, 2016-2019.

Objectives. To examine associations of current mental and substance use disorders with self-reported gun ownership and carrying among recently separated US Army soldiers. Veterans have high rates of both gun ownership and mental disorders, the conjunction of which might contribute to the high suicide rate in this group. Methods. Cross-sectional survey data were collected in 2018-2019 from 5682 recently separated personnel who took part in the Army Study to Assess Risk and Resilience in Servicemembers. Validated measures assessed recent mood, anxiety, substance use, and externalizing disorders. Logistic regression models examined associations of sociodemographic characteristics, service characteristics, and mental disorders with gun ownership and carrying. Results. Of the participants, 50% reported gun ownership. About half of owners reported carrying some or most of the time. Mental disorders were not associated significantly with gun ownership. However, among gun owners, major depressive disorder, panic disorder, posttraumatic stress disorder, and intermittent explosive disorder were associated with significantly elevated odds of carrying at least some of the time. Conclusions. Mental disorders are not associated with gun ownership among recently separated Army personnel, but some mental disorders are associated with carrying among gun owners. (Am J Public Health. 2021;111(10):1855-1864. https://doi.org/10.2105/AJPH.2021.306420).

Social closeness and support are associated with lower risk of suicide among U.S. Army soldiers.

OBJECTIVE: We tested the aspects of social support, unit cohesion, and religiosity hypothesized to be protective factors for suicide among U.S. service members. METHODS: This case-control study compared U.S. Army soldiers who died by suicide while on active duty (n = 135) to controls of two types: those propensity score-matched on known sociodemographic risk factors (n = 128); and those controls who had thought about, but not died by, suicide in the past year (n = 108). Data included structured interviews of next of kin (NOK) and Army supervisors (SUP) for each case and control soldier. Logistic regression analyses were used to examine predictors of suicide. RESULTS: Perceived social closeness and seeking help from others were associated with decreased odds of suicide, as reported by SUP (OR = 0.2 [95% CI = 0.1, 0.5]) and NOK (OR = 0.4 [95% CI = 0.2, 0.8]). Novel reports by SUP informants of high levels of unit cohesion/morale decreased odds of suicide (OR = 0.1 [95% CI = 0.0, 0.2]). Contrary to study hypotheses, no religious affiliation was associated with lower odds of suicide (OR = 0.3 [95% CI = 0.2, 0.6]). CONCLUSIONS: Perceived social closeness and unit/group cohesion are associated with lower odds of suicide. These results point toward social intervention strategies as testable components of suicide prevention programs.

Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder.

BACKGROUND: Evidence-based pharmacological treatments for posttraumatic stress disorder (PTSD) are few and of limited efficacy. Previous work suggests that angiotensin type 1 receptor inhibition facilitates fear inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the angiotensin type 1 receptor antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD. METHODS: A randomized controlled trial was conducted for 10 weeks in 149 men and women meeting DSM-5 PTSD criteria. Losartan (vs. placebo) was flexibly titrated from 25 to 100 mg/day by week 6 and held at highest tolerated dose until week 10. Primary outcome was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) change score at 10 weeks from baseline. A key secondary outcome was change in CAPS-5 associated with a single nucleotide polymorphism of the ACE gene. Additional secondary outcomes included changes in the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9, and proportion of responders with a Clinical Global Impressions-Improvement scale of "much improved" or "very much improved." RESULTS: Both groups had robust improvement in PTSD symptoms, but there was no significant difference on the primary end point, CAPS-5 measured as week 10 change from baseline, between losartan and placebo (mean change difference, 0.9, 95% confidence interval, -3.2 to 5.0). There was no significant difference in the proportion of Clinical Global Impressions-Improvement scale responders for losartan (58.6%) versus placebo (57.9%), no significant differences in changes in PTSD Checklist for DSM-5 or Patient Health Questionnaire-9, and no association between ACE genotype and CAPS-5 improvement on losartan. CONCLUSIONS: At these doses and durations, there was no significant benefit of losartan compared with placebo for the treatment of PTSD. We discuss implications for failure to determine the benefit of a repurposed drug with strong a priori expectations of success based on preclinical and epidemiological data.

Randomized Controlled Trial of Riluzole Augmentation for Posttraumatic Stress Disorder: Efficacy of a Glutamatergic Modulator for Antidepressant-Resistant Symptoms.

OBJECTIVE: Current pharmacologic treatments for posttraumatic stress disorder (PTSD) have shown limited efficacy, prompting a call to investigate new classes of medications. The current study investigated the efficacy of glutamate modulation with riluzole augmentation for combat-related PTSD symptoms resistant to treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: A randomized, double-blind, placebo-controlled, parallel trial was conducted at Walter Reed National Military Medical Center and Syracuse VA Medical Center between December 2013 and November 2017. Veterans and active duty service members with combat-related PTSD (per the Clinician Administered PTSD Scale [CAPS]) who were not responsive to SSRI or SNRI pharmacotherapy were randomized to 8-week augmentation with a starting dose of 100 mg/d of riluzole (n = 36) or placebo (n = 38) and assessed weekly for PTSD symptoms, anxiety, depression, disability, and side effects. RESULTS: Intent-to-treat analyses (N = 74) of the primary outcome (CAPS for DSM-IV) showed no significant between-group difference in change in overall PTSD symptoms (F = 0.64, P = .422), with a small effect size (d = 0.25). There was clinically significant within-group improvement in overall PTSD symptoms in both groups, with a greater mean (SD) decrease in CAPS score in the riluzole group (-21.1 [18.9]) than in the placebo group (-16.7 [17.2]). Exploratory analyses of PTSD symptom clusters showed significantly greater improvement on hyperarousal symptoms in the riluzole group as measured by the PTSD Checklist-Specific-Subscale D (d = 0.48) and near-significant findings on the CAPS Subscale D. Riluzole augmentation was not superior to placebo on change in depression, anxiety, or disability severity. CONCLUSIONS: Although preliminary, the exploratory findings of this study offer some evidence that riluzole augmentation of an SSRI or SNRI may selectively improve PTSD hyperarousal symptoms without changes in overall PTSD symptoms, depression, anxiety, or disability. Additional investigation of the mechanism of the efficacy of riluzole for hyperarousal symptoms is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02155829.