Clinician-Administered PTSD Scale Scores Research Articles

Elucidating trauma-related and disease-related regional cortical activity in post-traumatic stress disorder.

Trauma exposure may precipitate a cascade of plastic modifications within the intrinsic activity of brain regions, but it remains unclear which regions could be responsible for the development of post-traumatic stress disorder based on intrinsic activity. To elucidate trauma-related and post-traumatic stress disorder-related alterations in cortical intrinsic activity at the whole-brain level, we recruited 47 survivors diagnosed with post-traumatic stress disorder, 64 trauma-exposed controls from a major earthquake, and 46 age- and sex-matched healthy controls. All subjects were scanned with an echo-planar imaging sequence, and 5 parameters including the amplitude of low-frequency fluctuations, fractional amplitude of low-frequency fluctuations, regional homogeneity, degree centrality, and voxel-mirrored homotopic connectivity were calculated. We found both post-traumatic stress disorder patients and trauma-exposed controls exhibited decreased amplitude of low-frequency fluctuations in the bilateral posterior cerebellum and inferior temporal gyrus, decreased fractional amplitude of low-frequency fluctuation and regional homogeneity in the bilateral anterior cerebellum, and decreased fractional amplitude of low-frequency fluctuation in the middle occipital gyrus and cuneus compared to healthy controls, and these impairments were more severe in post-traumatic stress disorder patients than in trauma-exposed controls. Additionally, fractional amplitude of low-frequency fluctuation in left cerebellum was positively correlated with Clinician-Administered PTSD Scale scores in post-traumatic stress disorder patients. We identified brain regions that might be responsible for the emergence of post-traumatic stress disorder, providing important information for the treatment of this disorder.

Antidepressants in the acute treatment of post-traumatic stress disorder in adults: a systematic review and meta-analysis.

Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice. This meta-analysis aimed to review the efficacy of antidepressants in the acute treatment of PTSD in adults while investigating the contribution of study design and placebo response to the findings of these studies. Randomized, double-blind, placebo-controlled clinical trials that compared antidepressants with placebo for acute treatment of PTSD were selected. Standardized mean difference (SMD) in change in Clinician-Administered PTSD Scale scores were pooled after examining for heterogeneity. A random-effects meta-analysis was performed. Twenty-nine antidepressant-placebo comparisons, involving 4575 subjects, were analyzed. The SMD among all studies was 0.25, a small to medium effect size, lower than that in studies of antidepressants in adult major depressive disorder. The SMDs for low and high mean placebo responses, were 0.27 and 0.22, respectively. The overall SMD for paroxetine studies was in the moderate range (0.43) and that for sertraline studies was in the small range (0.12). Our findings suggest that antidepressants have modest efficacy in alleviating PTSD symptoms. Patient-level meta-analyses are required to further explore the potential clinical relevance of sertraline for PTSD.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ketamine.

Ketamine, an arylcyclohexylamine dissociative anesthetic agent, has evolved into a versatile therapeutic. It has a rapid-onset, well-understood cardiovascular effects and a favorable safety profile in clinical use. Its enantiomeric compound, esketamine, was approved by the Food and Drug Administration in 2019 for both treatment-resistant depression and major depressive disorder with suicidal ideation. Research indicates dose-dependent impacts on cognition, particularly affecting episodic and working memory following both acute administration and chronic use, albeit temporarily for the former and potentially persistent for the latter. Alongside acute risks to cardiovascular stability, ketamine use poses potential liver toxicity concerns, especially with prolonged or repeated exposure within short time frames. The drug's association with "ketamine cystitis," characterized by bladder inflammation, adds to its profile of physiological risks. Data demonstrate a single intravenous infusion of ketamine exhibits antidepressant effects within hours (weighted effect size averages of depression scores (N = 518) following a single 0.5 mg/kg infusion of ketamine is d = 0.96 at 24 hours). Ketamine is also effective at reducing posttraumatic stress disorder (PTSD) symptom severity following repeated infusions (Clinician-Administered PTSD Scale scores: -11.88 points compared with midazolam control). Ketamine also decreased suicidal ideation in emergency settings (Scale for Suicidal Ideation scores: -4.96 compared with midazolam control). Through its opioid-sparing effect, ketamine has revolutionized postoperative pain management by reducing analgesic consumption and enhancing recovery. Many studies indicate that ketamine's therapeutic effects may subside within weeks. Repeated administrations, given multiple times per week, are often required to sustain decreases in suicidality and depressive symptoms. Ketamine's comprehensive clinical profile, combined with its robust effects on depression, suicidal ideation, PTSD, chronic pain, and other psychiatric conditions, positions it as a substantial contender for transformative therapeutic application.

The Effect of Add-on Memantine in New Onset Combat-Related Posttraumatic Stress Disorder Core Symptoms: A Pilot Study.

Objective: Studies using standard neuropsychological instrumentation have shown memory deficits in posttraumatic stress disorder (PTSD) patients. We examined the efficacy and safety of memantine in new cases of combat-related PTSD in the military by conducting a 16-week prospective double-blind randomized controlled trial. Method : Twenty-six new combat-related PTSD cases were recruited from among the military personnel based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Patients were assigned to memantine and Placebo groups. They were monitored at baseline, week eight, and week 16. Memantine was added to each patient's current medication with an initial dosage of 5 mg/day, raised by 5 mg/day every week until it reached the maintenance level of 20 mg/day. The concurrent drugs were essentially kept unchanged during the trial. The primary outcome was PTSD severity as assessed by the Clinician-administered PTSD Scale (CAPS). The CAPS is a valid and reliable tool for the diagnosis of PTSD and measurement of its severity according to the DSM-4. Results: CAPS mean score in baseline (P = 0.811) and weeks eight (P = 0.389) and 16 (P = 0.066) did not show any significant differences between the two groups. The mean CAPS score in the memantine group significantly (P = 0.006) decreased (Mean differences = -8.79) compared to the placebo group, showing that intervention with memantine was effective. The mean total CAPS in weeks eight (Mean differences = -14.21) and 16 (Mean differences = -27) were less than the baseline, which was significantly meaningful (P < 0.001). Conclusion: Findings of this study suggest that add-on memantine can be effective in veteran patients with PTSD. So our data provide useful insight into the management of new cases of combat-related PTSD.

0423 The Role of Fear of Sleep in Cognitive Behavioral Therapy for Insomnia and Cognitive Processing Therapy

Abstract Introduction Fear of sleep (FoS) is linked to symptoms of PTSD. Additionally, cognitive behavioral therapy for insomnia (CBTi) can reduce FoS. Utilizing data from a randomized controlled trial of CBTi followed by Cognitive Processing Therapy for PTSD (CPT), this secondary data analysis sought to examine the relationship between FoS and PTSD symptoms, and how FoS is impacted by CBTi, in individuals exposed to interpersonal violence with PTSD. Additionally, we sought to extend the literature by examining whether FoS predicts the effect of subsequent CPT on PTSD severity or if CPT further reduces FoS. Methods A sample of 83 participants were randomly assigned to either receive sequential delivery of four weekly sessions of CBTi, which included modules to address FoS, followed by 12 weekly sessions of CPT (Group 1: CBTi+CPT) or receive four weekly phone check-ins (CTRL) followed by CPT (Group 2: CTRL+CPT). Participants were assessed at baseline (T1), after CBTi/CTRL (T2), and after CPT (T3). Relevant measures included the Fear of Sleep Inventory (FoSI) and Clinician Administered PTSD Scale (CAPS). Analyses included correlations, mean differences tests, and regression-based analyses. Results At T1 FoSI and CAPS were positively correlated (r = 0.47, p &amp;lt; 0.001). At T2 a significant reduction in FoSI scores was observed after CBTi/CTRL for Group 1 (t = 4.81, p &amp;lt; 0.001), but not Group 2, and a significant difference in FoSI scores between Group 1 and Group 2, all while controlling for baseline differences (F (1, 80) = 3.99, p &amp;lt; 0.05). Lastly, for the entire sample lower T2 FoSI scores predicted lower T3 CAPS scores (B = 0.42, p &amp;lt; 0.01) and FoS was not further reduced following CPT. Conclusion Results replicate previous work by demonstrating a positive relationship between FoS and PTSD severity. Additionally, FoSI was significantly reduced after CBTi. Lastly, lower levels of FoS predicted reduced PTSD symptoms following CPT, although CPT was not associated with significant reductions in FoS. Results highlight that CBTi that explicitly addresses FoS may reduce FoS, and findings also suggest that effectively reducing FoS prior to PTSD treatment may improve treatment outcomes. Support (if any) NIH/NINR R01 NR013909; VA Center of Excellence for Suicide Prevention

Association of age of adverse childhood experiences with thalamic volumes and post-traumatic stress disorder in adulthood.

Adverse childhood experiences (ACEs) have been linked to brain development and mental disorders, however, the impact of the age of occurrence of ACEs on thalamic volume and post-traumatic stress disorder (PTSD) after adult trauma remains unclear. This study assessed associations between ACEs at different ages to thalamic volumes and PTSD development following acute adult trauma. Seventy-nine adult trauma survivors were recruited immediately after trauma. Within 2 weeks of the traumatic event, participants completed the PTSD Checklist (PCL) to assess PTSD symptoms, the Childhood Trauma Questionnaire (CTQ) and Childhood Age Range Stress Scale (CARSS) to evaluate ACEs and perceived stress level at preschool (<6 years old) and school (6-13 years old) ages, and structural magnetic resonance imaging (sMRI) to measure thalamic volumes. Participants were divided into three groups: those who experienced no childhood trauma or stress (non-ACEs), those who experienced childhood trauma and stress onset at preschool ages (Presch-ACEs), and those who experienced childhood trauma and stress onset at school ages (Sch-ACEs). At 3 months, participants underwent PTSD symptom evaluation using the Clinician Administered PTSD Scale (CAPS). Adult trauma survivors in the Presch-ACEs group had higher CTQ and CAPS scores. In addition, survivors in the Presch-ACEs group had smaller thalamic volume compared to survivors in the non-ACEs and Sch-ACEs groups. Furthermore, smaller thalamic volume moderated a positive association between post-trauma 2-week PCL and subsequent 3-month CAPS scores. Earlier occurrence of ACEs was associated with smaller thalamic volume, which appears to moderate a positive association between early posttraumatic stress symptom severity and PTSD development after adult trauma. This raises the possibility that early occurrence of ACEs may impact thalamic structure, specifically a reduction in thalamic volume, and that smaller thalamic volume may contribute to susceptibility to PTSD development after adult trauma.

Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder

To date, no psychopharmacologic treatment has been found to be uniformly effective in veterans with posttraumatic stress disorder (PTSD); novel targets and approaches are needed to treat this disabling disorder. To examine whether treatment with the glucocorticoid receptor antagonist mifepristone yields a signal for clinical efficacy in male veterans with PTSD. This phase 2a, double-blind, parallel-group randomized clinical trial was conducted from November 19, 2012 (accrual started), through November 16, 2016 (final follow-up), within the US Department of Veterans Affairs. Participants were male veterans with chronic PTSD and a screening Clinician-Administered PTSD Scale score of 50 or higher. A total of 181 veterans consented to participation. Statistical analysis was conducted between August 2014 and May 2017. Participants were randomized in a 1:1 ratio to mifepristone (600 mg) or matched placebo taken orally for 7 days. The clinical outcome was whether a veteran achieved a clinical response status (a reduction of ≥30% of total Clinician-Administered PTSD Scale score from baseline) at 4- and 12-week follow-up. On the basis of a binary statistical selection rule, a difference in the proportion of treatment vs control group responders of 15% would be a clinically relevant difference. Self-report measures of PTSD and associated symptoms were also obtained. Neuroendocrine outcomes and plasma levels of mifepristone were measured. Safety was assessed throughout the study. The primary analysis was based on a multiple imputation technique to address missing outcome data; thus, some participant numbers may not appear as whole numbers. A total of 81 veterans were enrolled and randomized. Excluding 1 participant randomized in error, 80 were included in the modified intention-to-treat analysis (41 randomized to mifepristone and 39 to placebo). The mean (SD) age was 43.1 (13.7) years. A total of 15.6 (38.1%) in the mifepristone group and 12.1 (31.1%) in the placebo group were clinical responders at 4 weeks in the analysis using the multiple imputation technique. The group difference in the proportion of clinical responders (7.0%) was less than the predefined margin of 15% indicating signal for clinical efficacy. In an exploratory analysis, the difference in response to mifepristone vs placebo in the subgroup with no lifetime history of traumatic brain injury (TBI) (7.0 [50.0%] vs 3.0 [27.3%]; difference, 22.7%) exceeded the efficacy margin at 4 weeks and was sustained at 12 weeks. In contrast, in veterans with PTSD and lifetime TBI, the response rate to mifepristone was lower than placebo at 12 weeks (7.4 [27.4%] vs 13.5 [48.3%]; difference, -20.9%). This study did not detect a signal for efficacy for mifepristone at 600 mg/d for 1 week in male veterans with chronic PTSD. Thus, this study does not support a phase 3 trial in this population. Future studies of mifepristone for the treatment of PTSD may be of interest in those without a history of TBI or in samples with a low base rate of lifetime head trauma. ClinicalTrials.gov Identifier: NCT01946685.

Seeking safety intervention for comorbid post-traumatic stress and substance use disorder: A meta-analysis.

Seeking Safety (SS) is a widely implemented cognitive-behavioral therapy for comorbid post-traumatic stress disorder (PTSD) and substance use disorder (SUD). It is a present-focused coping skills model that is highly flexible, with varied methods of delivery, to maximize acceptability and client access. The purpose of this meta-analysis is to examine the effect of SS on comorbid PTSD and SUD across randomized control trials (RCTs). In addition, ours is the first meta-analysis to examine the dose-response of SS by comparing delivery of all 25 SS topics versus fewer. Articles published before January 2, 2023 (CINAHL n=16, PsycINFO n=31, MEDLINE n=27, Cochrane n=38, and Scopus n=618) were searched. Seven studies were included for meta-analysis and dose-response analysis. Based on effect sizes (ES), meta-analysis revealed that SS has a medium group, time (p=.04), and time by group effect on substance use per the Addiction Severity Index at 3 months and a small effect on Clinician-Administered PTSD Scale scores by group, a large effect by time, and a medium time by group (p=.002) effect at 6 months. Based on the pooled ES examining various measures across multiple timepoints, SS had small to medium effects on substance use by time, group, or time by group and medium to large effects on PTSD symptoms by time, group, or time by group (except for the group effect at 3-month follow-up). Significant effects were found for substance use by time at 3 and 6 months and for PTSD postintervention, at 6 months and 9 months by group, time, and time by group while only by time at 3 months. Meta-regression revealed that partial dose versions of SS generally function as well as the full dose version of SS when observing long-term effects (greater than 3 months). Findings suggest SS has merit in treating PTSD symptoms and SUD. Based on the summarized effect sizes, SS appears more effective in reducing PTSD than substance use, which converges with the larger treatment outcome literature that consistently finds this. We explore reasons that treatment of SUD is more challenging than treating PTSD and offer suggestions for practitioners. We emphasize the need for future studies to utilize common measures and provide full details of treatment delivery for optimal comparison across studies.

A proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist for PTSD: Design, methods, and recruitment

BackgroundAlmost eight million Americans suffer from Posttraumatic Stress Disorder (PTSD). Current PTSD drug therapies rely on repurposed antidepressants and anxiolytics, which produce undesirable side effects and have recognized compliance issues. Vasopressin represents a promising and novel target for pharmacological intervention. Logistical issues implementing a clinical trial for a novel PTSD pharmaceutical are relatively uncharted territory as trials concerning a new agent have not been published in the past several decades. All published trials have repurposed FDA-approved psychoactive medications with known risk profiles. Our recruitment challenges are discussed in this context. MethodsAn 18-week proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist (SRX246) for PTSD was conducted. All participants received SRX246 for 8 weeks, the placebo for 8 weeks, and the drug vs. placebo arms were compared. Participants were assessed every 2 weeks for PTSD symptoms as well as other medication effects. Results were expected to provide an initial demonstration of safety and tolerability in this clinical population and potentially clinical efficacy in SRX246-treated patients measured by Clinician Administered PTSD Scale (CAPS) score changes, clinical impression, and other indices compared to placebo. The primary hypothesis was that SRX246 would result in a clinically meaningful 10-point reduction in mean CAPS score compared to placebo. DiscussionThis study is the first to investigate an oral vasopressin 1a receptor antagonist for PTSD. As a wave of PTSD clinical trials with new pharmaceutical compounds are beginning now, lessons learned from our recruitment challenges may be invaluable to these endeavors.

A Study on the Factors Affecting Anger in Patients With Post-traumatic Stress Disorder.

To identify the factors affecting anger in post-traumatic stress disorder (PTSD) patients who underwent Clinician-Administered PTSD Scale (CAPS) and Minnesota Multiphasic Personality Inventory-2 (MMPI-2). We retrospectively reviewed patients who underwent CAPS and MMPI-2 at Veteran Health Service Medical Center, Seoul, Korea. Based on the CAPS score, the patients were divided into the PTSD group (n=46) and the trauma exposed without PTSD group (n=29). After checking the correlation between anger, CAPS, and MMPI-2 scales, logistic regression analysis was performed to identify the risk factors for clinically relevant symptoms. The PTSD group showed significant differences in schizophrenia-related symptoms, ideas of persecution, aggressiveness, psychoticism, and anger scales compared to the trauma-exposed without PTSD group. There was a significant correlation between anger, CAPS, and MMPI-2 except masculinity/femininity, disconstraint, and MacAndrew Alcoholism-Revised. In particular, anger has been shown to have a substantial connection with paranoia, schizophrenia-related symptoms, ideas of persecution, aberrant experiences, and psychoticism. Multiple regression analysis identified that the only significant risk factor for anger was the negative emotionality/neuroticism scale (odds ratio=1.152, p<0.001). The PTSD group had increased anger compared to the trauma-exposed without PTSD group, and that negative emotions may be a risk factor for PTSD.

Findings from a pilot study of Trauma Center Trauma-Sensitive Yoga versus cognitive processing therapy for PTSD related to military sexual trauma among women Veterans

ObjectiveThe study objective was to explore the preliminary efficacy of trauma-sensitive yoga compared to cognitive processing therapy (CPT) for women Veterans with posttraumatic stress disorder (PTSD) related to military sexual trauma (MST) in a pilot randomized control trial (RCT). We then compared these results to published interim results for the subsequent full-scale RCT. MethodThe analytic sample included women Veterans (N = 41) with PTSD related to MST accessing healthcare in a southeastern Veterans Affairs Health Care System. The majority were African American, non-Hispanic (80.5 %). The protocol-driven group interventions, Trauma Center Trauma-Sensitive Yoga (TCTSY; n = 17) and the evidence-based control condition, CPT (n = 24), were delivered weekly for 10 and 12 sessions, respectively. Multilevel linear models (MLM) were used to compare changes over time between the two groups. ResultsThe primary outcomes presented here are PTSD symptom severity and diagnosis, assessed using the Clinician Administered PTSD Scale (CAPS) and the PTSD Symptom Checklist (PCL) total scores. PTSD symptom severity on both clinician-administered (CAPS) and self-reported (PCL) measures, improved significantly (p < .005) over time, with large within group effect sizes (0.90–0.99) consistent with the subsequent RCT. Participants in the TCTSY group showed clinically meaningful improvements earlier than the CPT group participants from baseline on the CAPS and PCL Total scores. ConclusionsResults support published findings of the effectiveness of TCTSY in the treatment for PTSD related to MST among women Veterans, particularly African American women. TCTSY warrants consideration as an adjunctive, precursor, or concurrent treatment to evidence-based psychotherapies. Future research should include patient preference, men with sexual trauma, and civilian populations.

Combining Trauma Script Exposure With rTMS to Reduce Symptoms of Post-Traumatic Stress Disorder: Randomized Controlled Trial

BackgroundInnovative therapeutic interventions for post-traumatic stress disorder (PTSD) are required. We opted to facilitate fear extinction by combining trauma script exposure with repetitive transcranial magnetic stimulation (rTMS) to reduce symptoms of PTSD. ObjectiveThe efficacy and safety of 10 Hz rTMS of the right dorsolateral prefrontal cortex simultaneously with exposure to personal traumatic narrative were studied in patients with PTSD. Materials and MethodsThis trial was a single-center randomized controlled trial (NCT02584894). Patients were randomly assigned 1:1 to receive eight daily sessions of 110% of motor threshold high frequency (HF) 10 Hz rTMS (110% HF rTMS) or 70% low frequency (LF) 1 Hz rTMS (70% LF rTMS) with trauma script exposure in both groups. Severity of PTSD, depression, and anxiety were assessed before and after study treatment (one month, three months) by an assessor masked to the trial group assignment. The primary outcome was the severity of PTSD assessed by the Clinician Administered PTSD Scale (CAPS). We used mixed linear regression models for statistical comparisons. ResultsThirty-eight patients (65.8% females) were randomly assigned to 110% HF rTMS (n = 18, 31.3 ± 10.0 years, 13 females) or 70% LF rTMS (n = 20, 33.5 ± 11.1 years, 12 females). From baseline to three months, mean CAPS scores decreased by 51% in the 110% HF rTMS group (from 83.7 ± 14.4 to 41.8 ± 31.9) and by 36.9% in the 70% LF rTMS group (from 81.8 ± 15.6 to 51.6 ± 23.7), but with no significant difference in improvement (time by treatment interaction −3.61 [95% confidence interval (CI), −9.70 to 2.47]; p = 0.24; effect size 0.53). One serious adverse event occurred during the study (psychogenic nonepileptic seizure). ConclusionWe found no evidence of difference in clinical improvement or remission rates between the 110% HF and 70% LF stimulation. These findings may reflect the importance of exposure procedure and that larger number of participants is needed.

Atomoxetine in comorbid ADHD/PTSD: A randomized, placebo controlled, pilot, and feasibility study.

PTSD and ADHD often occur comorbidly. Research indicates that the cognitive deficits in PTSD may be related to the same disturbance of fronto-temporal systems as observed in ADHD, and ADHD has been shown to impact PTSD treatment outcomes. The presented study evaluated the safety and efficacy of atomoxetine in Veterans with comorbid ADHD/PTSD. A double blind, randomized, placebo controlled, cross-over pilot and feasibility study was conducted. Atomoxetine was examined as an adjunctive treatment over this 10 weeks, two phase, crossover study which compared treatment with atomoxetine 80 mg daily to placebo daily. The primary outcome was improvement in ADHD symptoms as measured by the Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S), the Barkley Adult ADHD Rating Scale-IV (BAARS-IV), and the Adult ADHD Quality of Life-29 (AAQoL-29). Secondary outcomes included the Clinician Administered PTSD Scale (CAPS), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the response inhibition task Go/NoGo (GNG). Atomoxetine treated patients had greater reductions in ADHD symptoms as defined by total scores on the CAARS-S:S (F(1, 29) = 6.37, p = .017); both the BAARS-IV (F(1, 26) = 3.16, p = .087); and GNG overall errors test (F(1, 29) = 3.88, p = .06), reached a trend level of significance. No significant differences were noted in quality of life assessments, GNG latency periods, or CAPS scores. Atomoxetine was well-tolerated with no serious adverse events observed. In Veterans with ADHD comorbid with PTSD, atomoxetine demonstrated modest efficacy for ADHD symptoms; quality of life measures and PTSD symptoms were not affected.

Altered gene expression and PTSD symptom dimensions in World Trade Center responders.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p < 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Post-Traumatic Stress Disorder (PTSD) biomarker identification using a deep learning model

Post-traumatic stress disorder (PTSD) is a neuropsychological disorder in which individuals struggle to recover from a traumatizing event. It affects a significant population, including COVID-19 patients, frontline health workers, and war veterans. Given biases associated with self-assessment and diagnosis of PTSD, researchers are actively searching for unbiased biological markers (biomarkers) for predicting PTSD status. The Systems Biology of PTSD Consortium has collected candidate biomarkers for PTSD using molecular and clinical measurements of male war veterans between the ages of 20 and 60. PTSD-positive and negative subjects were separated based on the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Clinician Administered PTSD Scale (CAPS) scores, derived from structured interviews to measure an individual’s abundance of symptoms, such as re-experiencing, flashbacks, and hyperarousal. CAPS scores higher than 40 were considered PTSD-positive and below 20 were considered negative. We created artificial neural network models to classify PTSD-positive and negative individuals based on metabolomics, micro-RNA (miRNA), protein expression, endocrine markers, and DNA methylation datasets. Model training involved 64 iterations of a Bayesian Hyperparameter Optimization algorithm with 5-fold cross-validation. Each model was calibrated based on cross-validation performance and variance across iterations and then fit to the entire respective dataset (76 PTSD-positive, 76 PTSD-negative). We applied the trained models to an independent validation cohort to assess accuracy on unseen datasets. The top performing datasets from the validation cohort based on classification accuracy were metabolomics (65.2%) and protein expression (61.8%). We anticipate the candidate biomarkers identified in this and future studies will assist with the diagnosis of PTSD.

MDMA‐Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta‐Analysis

This article discusses current literature on the use of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in the treatment of posttraumatic stress disorder (PTSD). MDMA, the intended active ingredient in illicit Ecstasy or Molly products, is a psychedelic that causes an elevated mood, feeling of bonding, and increased energy. In MDMA-assisted psychotherapy, patients are subjected to 2 or 3 multihour sessions of therapy with a team of psychiatrists. The dosing of MDMA is used to allow the therapist to probe the underlying trauma without causing emotional distress. The use of MDMA-assisted psychotherapy treatment reduced patient's Clinician-Administered PTSD Scale (CAPS) scores from baseline more than control psychotherapy (-22.03; 95%CI, -38.53 to -5.52) but with high statistical heterogeneity. MDMA-assisted psychotherapy enhanced the achievement of clinically significant reductions in CAPS scores (relative risk, 3.65; 95%CI, 2.39-5.57) and CAPS score reductions sufficient to no longer meet the definition of PTSD (relative risk, 2.10; 95%CI, 1.37-3.21) with no detected statistical heterogeneity. While therapy was generally safe and well tolerated, bruxism, anxiety, jitteriness, headache, and nausea are commonly reported. While MDMA-assisted psychotherapy has been shown to be an effective therapy for patients with PTSD with a reasonable safety profile, use of unregulated MDMA or use in the absence of a strongly controlled psychotherapeutic environment has considerable risks.

Association Between Posttraumatic Stress Disorder and Epigenetic Age Acceleration in a Sample of Twins.

Posttraumatic stress disorder (PTSD) has been related to accelerated biological aging processes, but objective evidence for this association is limited. DNA methylation (DNAm) age acceleration is a novel measure of biological aging that may help clarify if PTSD is related to biological aging processes. We aim to examine whether PTSD is associated with biological aging using a comprehensive set of DNAm age acceleration markers and to what extent the unshared environment contributes to the association. Using a cross-sectional co-twin control study design, we investigated the association of the clinical diagnosis and symptom severity of PTSD with six measurements of DNAm age acceleration based on epigenome-wide data derived from peripheral blood lymphocytes of 296 male twins from the Vietnam Era Twin Registry. Twins with current PTSD had significantly advanced DNAm age acceleration compared with twins without PTSD for five of six measures of DNAm age acceleration. Across almost all measures of DNAm age acceleration, twins with current PTSD were "epigenetically older" than their twin brothers without PTSD: estimated differences ranged between 1.6 (95% confidence interval = 0.0-3.1) and 2.7 (95% confidence interval = 0.5-4.8) biological age year-equivalents. A higher Clinician-Administered PTSD Scale score was also associated with a higher within-pair DNAm age acceleration. Results remained consistent after adjustment for behavioral and cardiovascular risk factors. PTSD is associated with epigenetic age acceleration, primarily through unshared environmental mechanisms as opposed to genetic or familial factors. These results suggest that PTSD is related to systemic processes relevant to biological aging.

Combining Deep Learning and Graph-Theoretic Brain Features to Detect Posttraumatic Stress Disorder at the Individual Level.

Previous studies using resting-state functional MRI (rs-fMRI) have revealed alterations in graphical metrics in groups of individuals with posttraumatic stress disorder (PTSD). To explore the ability of graph measures to diagnose PTSD and capture its essential features in individual patients, we used a deep learning (DL) model based on a graph-theoretic approach to discriminate PTSD from trauma-exposed non-PTSD at the individual level and to identify its most discriminant features. Our study was performed on rs-fMRI data from 91 individuals with PTSD and 126 trauma-exposed non-PTSD patients. To evaluate our DL method, we used the traditional support vector machine (SVM) classifier as a reference. Our results showed that the proposed DL model allowed single-subject discrimination of PTSD and trauma-exposed non-PTSD individuals with higher accuracy (average: 80%) than the traditional SVM (average: 57.7%). The top 10 DL features were identified within the default mode, central executive, and salience networks; the first two of these networks were also identified in the SVM classification. We also found that nodal efficiency in the left fusiform gyrus was negatively correlated with the Clinician Administered PTSD Scale score. These findings demonstrate that DL based on graphical features is a promising method for assisting in the diagnosis of PTSD.

Dysconnectivity of the amygdala and dorsal anterior cingulate cortex in drug-naive post-traumatic stress disorder

Convergent studies have highlighted the amygdala-based and dorsal anterior cingulate cortex (dACC)-based circuit or network dysfunction in post-traumatic stress disorder (PTSD). However, previous studies are often complicated by various traumatic types, psychiatric comorbidities, chronic illness duration, and medication effect on brain function. Besides, little is known whether the functional integration with amygdala–dACC interaction disrupted or not in PTSD. Here, we investigated effective connectivity (EC) between the amygdala-dACC and rest of the cortex by applying psycho-physiological interaction (PPI) approach to resting-state functional magnetic resonance imaging data of 63 drug-naive PTSD patients and 74 matched trauma-exposed non-PTSD controls. Pearson correlation analysis was performed between EC values extracted from regions with between-group difference and clinical profiles in PTSD patients. We observed distinct amygdala-dACC interaction pattern between PTSD group and the control group, which is composed primarily by positive EC in the former and negative in the latter. In addition, compared with non-PTSD controls, PTSD patients showed increased EC between amygdala-dACC and the prefrontal cortex, left inferior parietal lobule, and bilateral ventral occipital cortex, and decreased EC between amygdala-dACC and the left fusiform gyrus. The EC increase between amygdala-dACC and the right middle frontal gyrus was negatively correlated with the clinician-administered PTSD scale scores in PTSD patients. Aberrent communication between amgydala-dACC and brain regions involved in central executive network and visual systems might be associated with the pathophysiology of PTSD. Further, these findings suggested that dysconnectivity of the amygdala and dACC could be adapted as a relatively early course diagnostic biomarker of PTSD.

A Randomized Clinical Trial of Cognitive-Behavioral Therapy for Insomnia to Augment Posttraumatic Stress Disorder Treatment in Survivors of Interpersonal Violence

Introduction: Individuals exposed to interpersonal violence (IPV) commonly develop posttraumatic stress disorder (PTSD) with co-occurring depression and insomnia. Standard PTSD interventions such as cognitive processing therapy (CPT) do not typically lead to remission or improved insomnia. Cognitive behavioral therapy for insomnia (CBTi) improves insomnia in individuals with PTSD, but PTSD severity remains elevated. Objective: To determine whether sequential treatment of insomnia and PTSD is superior to treatment of only PTSD. Methods: In a 20-week trial, 110 participants exposed to IPV who had PTSD, depression and insomnia were randomized to CBTi followed by CPT or to attention control followed by CPT. Primary outcomes following CBTi (or control) were the 6-week change in score on the Insomnia Severity Index (ISI), the Clinician-Administered PTSD Scale (CAPS), and the Hamilton Rating Scale for Depression (HAM-D). Primary outcomes following CPT were the 20-week change in scores. Results: At 6 weeks, the CBTi condition had greater reductions in ISI, HAM-D, and CAPS scores than the attention control condition. At 20 weeks, participants in the CBTi+CPT condition had greater reductions in ISI, HAM-D, and CAPS scores compared to control+CPT. Effects were larger for insomnia and for depression than for PTSD. Similar patterns were observed with respect to clinical response and remission. A tipping point sensitivity analyses supported the plausibility of the findings. Conclusions: The sequential delivery of CBTi and CPT had plausible, significant effects on insomnia, depression, and PTSD compared to CPT alone. The effects for PTSD symptoms were moderate and clinically meaningful.