Post-traumatic stress disorder: the role of the amygdala and potential therapeutic interventions - a review.

Introduction: Post-traumatic stress disorder (PTSD) is a psychiatric disorder triggered by exposure to a life-threatening or sexually violent traumatic event, and is characterized by symptoms involving intrusive re-experiencing, persistent avoidance of associated stimuli, emotional and cognitive disturbances, and hyperarousal for long periods after the trauma has occurred. These debilitating symptoms induce occupational and social impairments that contribute to a significant clinical burden for PTSD patients, and substantial socioeconomic costs, reaching approximately $20,000 dollars per individual with PTSD each year in the US. Despite increased translational research focus in the field of PTSD, the development of novel, effective pharmacotherapies for its treatment remains an important unmet clinical need. Observations: In this review, we summarize the evidence implicating dysfunctional activity of the amygdala in the pathophysiology of PTSD. We identify the transient receptor potential canonical (TRPC) ion channels as promising drug targets given their distribution in the amygdala, and evidence from animal studies demonstrating their role in fear response modulation. We discuss the evidence-based pharmacotherapy and psychotherapy treatment approaches for PTSD. Discussion: In view of the prevalence and economic burden associated with PTSD, further investigation is warranted into novel treatment approaches based on our knowledge of the involvement of brain circuitry and the role of the amygdala in PTSD, as well as the potential added value of combined pharmacotherapy and psychotherapy to better manage PTSD symptoms.

A Neuroanatomic and Pathophysiologic Framework for Novel Pharmacological Approaches to the Treatment of Post-traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a debilitating disorder inflicting high degrees of symptomatic and socioeconomic burdens. The development of PTSD results from a cascade of events with contributions from multiple processes and the underlying pathophysiology is complex, involving neurotransmitters, neurocircuitry, and neuroanatomical pathways. Presently, only two medications are US FDA-approved for the treatment of PTSD, both selective serotonin reuptake inhibitors (SSRIs). However, the complex underlying pathophysiology suggests a number of alternative pathways and mechanisms that may be targets for potential drug development. Indeed, investigations and drug development are proceeding in a number of these alternative, non-serotonergic pathways in an effort to improve the management of PTSD. In this manuscript, the authors introduce novel and emerging treatments for PTSD, including drugs in various stages of development and clinical testing (BI 1358894, BNC-210, PRAX-114, JZP-150, LU AG06466, NYV-783, PH-94B, SRX246, TNX-102), established agents and known compounds being investigated for their utility in PTSD (brexpiprazole, cannabidiol, doxasoin, ganaxolone, intranasal neuropeptide Y, intranasal oxytocin, tianeptine oxalate, verucerfont), and emerging psychedelic interventions (ketamine, MDMA-assisted psychotherapy, psilocybin-assisted psychotherapy), with an aim to examine and integrate these agents into the underlying pathophysiological frameworks of trauma-related disorders.

Biomechanical effects of fatigue on lower-body extremities during a maximum effort kettlebell swing protocol.

Kettlebell training provides multiple health benefits, including the generation of power. The primary purpose of this study was to examine the kinematics and kinetics of lower-body joints during a repeated, maximum effort kettlebell swing protocol. Sixteen resistance and kettlebell swing experienced males performed 10 rounds of a kettlebell swing routine (where one round equates to 30s of swings followed by 30s of rest). Kinematic (i.e., swing duration and angular velocities) and kinetic (i.e., normalised sagittal plane ground reaction force, resultant joint moment [RJM] and power) variables were extracted for the early portion and late portion of the round. Average swing duration and the magnitude of normalised ground reaction forces (GRF) increased within rounds, while hip joint power decreased. Changes in swing duration were minimal, but consistent due to an increase in overall fatigue. An increase in the magnitude of GRF was observed at the end of rounds, which is a potential concern for injury. Hip joint power decreased primarily due to a slower angular velocity. This protocol may be an effective routine for those who are resistance trained with kettlebell swing experience, and who want to optimise power in their exercise program.

A Double-Blind Randomized Controlled Trial of Doxazosin for Co-Occurring PTSD and Alcohol Use Disorder in Veterans.

Objective: The aim of this study was to determine the efficacy of doxazosin, an α1-adrenergic antagonist, for the treatment of co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD).Methods: This 12-week, double-blind, randomized controlled trial of doxazosin (16 mg/d) was conducted between June 2016 and December 2019 at the Ralph H. Johnson VA Medical Center in Charleston, South Carolina. Participants were military veterans (N = 141) who met DSM-5 criteria for current PTSD and AUD and were randomly assigned to receive doxazosin (n = 70) or placebo (n = 71). Primary outcome measures were the Clinician Administered PTSD Scale (CAPS-5), the PTSD Checklist for DSM-5 (PCL-5), and the Timeline Follow-Back (TLFB).Results: Findings from the intent-to-treat analyses revealed that participants in both groups demonstrated statistically significant reductions in CAPS-5 and PCL-5 scores (P < .0001), but, contrary to hypotheses, no significant differences were observed between groups. Percent drinking days and percent heavy drinking days also decreased significantly during treatment, but there were no differences between groups (P < .0001). Abstinence during treatment was significantly higher in the doxazosin versus the placebo group (22% vs 7%, P = .017); however, participants in the doxazosin group consumed a greater number of drinks on drinking days (6.15 vs 4.56, P = .0096). A total of 74.5% of the sample completed the treatment phase, and there were no group differences in retention or adverse events.Conclusions: Doxazosin was safe and tolerable but was not more effective than placebo in reducing PTSD or AUD severity in this dually diagnosed sample. Clinical considerations such as heterogeneity of PTSD and AUD presentation and potential moderators are discussed in the context of future research directions.Trial Registration: ClinicalTrials.gov Identifier: NCT02500602.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

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

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: In Veterans with ADHD comorbid with PTSD, atomoxetine demonstrated modest efficacy for ADHD symptoms; quality of life measures and PTSD symptoms were not affected.

Biomarker Response to Mindfulness Intervention in Veterans Diagnosed with Post-traumatic Stress Disorder.

Objectives: This study evaluates the effects of treatment with mindfulness-based stress reduction (MBSR) compared to the active control, present-centered group therapy (PCGT), on morning plasma cortisol, interleukin-6 (IL-6), and C-reactive protein (CRP) in veterans diagnosed with post-traumatic stress disorder (PTSD). Methods: In a post hoc exploratory analysis, we pooled biomarkers and clinical outcomes of mindfulness, PTSD, and depression from two randomized controlled trials comparing MBSR (n = 104) to PCGT (n = 106) in U.S. military veterans diagnosed with PTSD. Linear mixed-effects modeling was used to evaluate associations between changes in biomarkers and clinical outcomes from baseline to 9-week primary endpoint and 16-week follow-up endpoint. Results: Cortisol levels were inversely related to self-reported PTSD symptoms at baseline (p = 0.02). Cortisol increased from baseline to 9-week endpoint for both groups, but significantly less so in the MBSR group compared to PCGT group (mean difference 1.69 ± 0.8 SE; p = 0.035). Changes in IL-6 and CRP did not differ between groups at either baseline or week 9. From baseline to week 9, increased mindfulness was significantly associated with increased cortisol (p = 0.02) and decreased PTSD and depression severity (p < 0.01). Increased IL-6 and CRP were significantly associated with decreased PTSD severity (p < 0.05), but not depression. Pooled analysis corroborated earlier findings that MBSR is significantly better than PCGT in improving clinical outcomes. Increased mindfulness was strongly associated with improved symptoms. Conclusions: Increased mindfulness is associated with a recalibration of cortisol levels which may be indicative of therapeutic response, especially in patients with lower baseline cortisol. Furthermore, mindfulness-based practices improve symptoms of PTSD and depression in a significant correlation with self-reported levels of mindfulness. Clinical Trial Registration clinicaltrialsgov: NCT01532999 and NCT01548742.

Dopamine transporter (DAT1) gene in combat veterans with PTSD: A case-control study.

The dopamine transporter (DAT1) gene has been postulated to be involved in PTSD; however, existing studies have shown inconsistencies when examining genotypic and allelic associations. The primary objective of this study was to examine whether DAT1-40bp-VNTR (DAT1) 9R polymorphism might increase the risk of PTSD development in combat veterans, utilizing a case-control gene association study with both control and PTSD cases having previous exposure to combat traumas. Participants with PTSD (N = 365) and combat-exposed controls without PTSD (N = 298) were included in analysis. After controlling for race, sex and age, when dichotomized, absence of DAT1 10R/10R genotypes was associated with PTSD diagnosis compared to no PTSD diagnosis; these results were not statistically significant when trichotomized 10R/10R, 10R/X, 9R/9R. Similarly, odds ratio for absence of 10R/10R genotype showed a statistically significant increase in the risk of developing PTSD. DAT1 genotype was also associated with statistically significant mean total CAPS scores, both when dichotomized and trichotomized. In conclusion, our results indicate that the absence of 10R/10R is associated with an increased risk of PTSD and higher CAPS total scores.

Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial.

Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks after TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with an exploratory double-blind phase of an additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified American Congress of Rehabilitation Medicine criteria for mild TBI with verbal memory deficits, as assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R). Patients were randomized 1:1 to rivastigmine or matching placebo patches after a 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24 h rivastigmine patches or matching placebo increased to a 9.5 mg/24 h patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least a five-word improvement on the HVLT-R Total Recall Index (Trials 1-3). A total of 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized, and 94 included in study analyses. Responder rates were 40.8% (20 of 49) and 51.1% (23 of 45) in the rivastigmine and placebo groups, respectively (p = 0.41). A mixed-effect model including treatment, time, and treatment-by-time interaction indicated no significant difference in treatment effect over time between the groups (p = 0.24). Overall, there were no significant differences in changes for all secondary outcomes between the rivastigmine and placebo groups. The most commonly observed adverse events were application site reactions. This trial provides the largest sample to date of veterans with TBI and post-traumatic memory deficits enrolled in a pharmacological trial. Trial Registration: clinicaltrials.gov Identifier: NCT01670526.

Cortisol awakening response in PTSD treatment: Predictor or mechanism of change.

PTSD is associated with abnormalities in hypothalamic-pituitary-adrenal (HPA) axis activity. This includes enhanced HPA axis negative feedback, attenuated cortisol awakening response, and attenuated cortisol response to personal trauma script. Whether HPA axis function predicts treatment response or treatment related symptom reduction in PTSD remains unclear. In addition, the relative effects of different treatment modalities (i.e., medication and psychotherapy) on HPA axis is unclear. To address this gap in knowledge, the PROGrESS study examined cortisol awakening response across treatment in Veterans with chronic PTSD randomized to receive Prolonged Exposure + Placebo (PE + PLB), Sertraline + PE (SERT + PE) or Sertraline + Enhanced Medication Management (SERT + EMM). Salivary cortisol awakening response (CAR) was assessed at baseline, mid-treatment (week 6 and 12), post-treatment (week 24) and follow-up (week 36 and 52). Among males at baseline, combat veterans with PTSD showed lower CAR Area Under the Curve Increase (AUCi; M = 3.15, SD = 9.57) than Combat controls (M = 7.63, SD = 9.07; p = .02), demonstrating combat veterans with PTSD have a less responsive system than combat controls. Higher PTSD severity was also related to lower CAR AUCi (r = -0.52, p = .03). When controlling for PTSD severity, higher baseline CAR AUCi was related to attenuated reduction in PTSD and lower likelihood of high treatment response over treatment (z = -2.06, p = .04).

A Bayesian Approach to Gateway Course Identification With Implications for the Prenursing Curriculum.

BACKGROUND: Analysis of student performance in gateway courses has been an important predictor of successful admission into upper-division nursing. PURPOSE: The aim was to explore the utility of a Bayesian statistical framework for determining threshold grades in prenursing courses that serve as gateways for successful admission into upper-division nursing programs. METHODS: Records of 3500 prenursing students who entered the prenursing program of a midsized public university during the past decade were analyzed. The Bayesian framework was used to incorporate conditional probabilistic concepts of sensitivity and specificity to calculate gateway impact of various grade level cutoffs on successful upper-division nursing admission. RESULTS: Identification, sequencing, and combination of grades attained in these gateway courses revealed different pathways to successful admission into upper-division nursing based on first-semester grade point average and ethnicity. CONCLUSIONS: Identification of primary/secondary gateway courses enhances successful matriculation and provides valuable information for advisors and curriculum planners for prenursing majors.

Ziprasidone Augmentation of SSRI Antidepressants in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Pilot Study of Augmentation Therapy.

BACKGROUND: Posttraumatic stress disorder (PTSD) is often a chronic, disabling illness for which antidepressant medications (ie, SSRI) are considered the primary psychopharmacological treatment. However, many patients remain refractory to antidepressants alone or in combination with psychotherapy. Safe and effective treatments for individuals with refractory PTSD are needed. This study aimed to examine ziprasidone augmentation of SSRI treatment of PTSD. METHODS: This was a 2-phase study. In phase 1, subjects were treated with paroxetine or sertraline for 8 weeks. Individuals refractory to the SSRI treatment then entered into phase II of the study and were randomized, in a double-blind fashion, to 8 weeks of treatment with either ziprasidone or placebo. The primary outcome measure was change in Clinician Administered PTSD Scale total scores with the intent-to-treat sample. Secondary outcome measures included Positive and Negative Syndrome Scale scores, measures of depression and anxiety, and safety measures. RESULTS: No significant differences were observed on the Clinician Administered PTSD Scale, Positive and Negative Syndrome Scale, or other outcome measures between ziprasidone and placebo groups. No significant differences were observed for safety measures including metabolic profiles, extrapyramidal symptoms/movement disorder rating scales, nor study dropout. CONCLUSIONS: Although no significant differences were noted in efficacy or safety measures between ziprasidone and placebo in this pilot study, the small sample size prevents definitive conclusions.

A Multisite Randomized Controlled Trial of Mindfulness-Based Stress Reduction in the Treatment of Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is often difficult to treat, and many patients do not achieve full remission. Complementary and integrative health approaches, such as mindfulness meditation, are intended to be integrated with evidence-based treatment. This study examined the efficacy of mindfulness-based stress reduction (MBSR) in the treatment of PTSD in U.S. military veterans. METHODS: Veterans with a diagnosis of PTSD (N=214) were randomly assigned to either 90-minute group MBSR or present-centered group therapy (PCGT) for eight weeks. Follow-up assessments were obtained at baseline and weeks 3, 6, 9 (primary endpoint), and 16. RESULTS: Both the MBSR and PCGT groups achieved significant improvement in PTSD as measured by the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV), with no statistically significant differences between groups. However, compared with PCGT, the MBSR group showed a statistically significant improvement in PTSD on the self-reported PTSD Checklist for DSM-IV over the nine weeks. This difference was not maintained posttreatment, at week 16. Strengths of the study include its large sample size, multisite design, active control group, single-blind outcome ratings, fidelity monitoring, large minority representation, and randomized approach. The study was limited by its high attrition rate and low representation of women. CONCLUSION: Both MBSR and PCGT appear to have beneficial effects in treating PTSD in veterans, with greater improvement observed in self-reported PTSD symptoms in the MBSR group. No differences between groups were observed on the CAPS-IV scale.

Successful Modeling of Factors Related to Recruitment and Retention of Prenursing Students.

BACKGROUND: The traditional admission methodology used by many schools of nursing is the second-tier admission based on specified criteria. This method has been associated with a student body that is predominately female, white, and English speaking. PROBLEM: Rational judgment modeling (points assigned to criteria) used to evaluate applicants for admission into prenursing programs potentially overlooks students who do not fit into the traditional model. APPROACH: This study compared predictive logistic regression with traditional rational judgment models to classify potential nursing school applicants. OUTCOMES: A higher number of Hispanic and black prenursing students were identified for potential upper-level nursing program admission. CONCLUSIONS: The use of logistic regression modeling can identify a more diverse student population. Advisors at both high school and university/college levels can use results of this model to help students determine their progress, identify academic weaknesses, and develop individual plans of action to help students successfully complete the prenursing curriculum requirements.

Posttraumatic stress disorder with secondary psychotic features (PTSD-SP): Diagnostic and treatment challenges.

Trauma exposure leads to various psychiatric disorders including depression, anxiety, bipolar disorders, personality disorders, psychotic disorders, and trauma related disorders, especially posttraumatic stress disorder (PTSD). There are some overlapping symptoms of both PTSD and psychosis that make diagnosis challenging. Despite this overlap, the evidence of PTSD with comorbid psychosis as a distinct entity lies in the research showing biologic, genetic and treatment management differences between psychotic PTSD, non-psychotic PTSD, psychotic disorders and healthy controls. There is emerging evidence that PTSD with secondary psychotic features (PTSD-SP) might be a discrete entity of PTSD with known risk factors that increase its prevalence. This review has presented evidence for individuals with PTSD-SP being distinct in genetics and neurobiological factors. Individuals with PTSD and comorbid psychosis can benefit from evidence based psychotherapy (EBT). There is not enough evidence to recommend second generation antipsychotics (SGA) for PTSD-SP given that risperidone and quetiapine are the only SGAs studied in randomized controlled trials. Hence, developing an operational diagnostic criteria and treatment framework for clinical and research use is critical.

Predictors of Lifetime Suicide Attempts in Individuals With Attenuated Psychosis Syndrome.

BACKGROUND: A strong association has been shown to exist between schizophrenia and suicide; however, research examining suicidality in the prodromal phase of psychotic disorders is limited. This study aimed to meet this need by examining potential risk factors for lifetime suicide attempts in a population of individuals with attenuated psychosis syndrome (APS), as defined in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders as a condition for further study. METHODS: A retrospective chart review was conducted to identify individuals with APS during a 5-year period across a large medical university's inpatient and outpatient settings. Sociodemographic and clinical factors were examined in relation to suicide attempts to identify risk factors for suicide attempts. χ analyses were used to analyze dichotomous variables, and t test analyses were used to compare means of continuous predictors among those with versus without suicide attempts. Final analyses consisted of fitting multivariate logistic regression models to control for sociodemographic factors. RESULTS: In total, 26.3% of the APS population had at least 1 lifetime suicide attempt. Six covariates were found to be statistically significant predictors of suicide attempts: Axis II disorders (P=0.006); history of trauma as a whole (P=0.022); the subcategory of sexual trauma (P=0.005); tobacco use (P=0.039); family history of nonpsychotic Axis I disorders (P=0.042); and number of hospitalizations (P=0.001). CONCLUSIONS: Suicidality is a prominent feature of APS, and a number of risk factors increase the likelihood of suicide attempts in this population.

Characterizing the Effects of Quetiapine in Military Post-Traumatic Stress Disorder.

Objectives: A previous randomized placebo-controlled trial in military veterans posttraumatic stress disorder (PTSD) found that quetiapine improved global PTSD symptoms severity, depression and anxiety as well as the re-experiencing and hypearousal clusters. However, it is not known if individual symptoms had a preferential response to this medication. The goal of this study was to analyze the individual symptom response in this group of patients. Methods: Data from a previous trial was re-analyzed. Each of the of the scale items was analyzed individually using Repeated Measures Analysis of Variance. Results: Compared to placebo, there was a significant decline in the Clinician-Administered PTSD Scale intrusive memories and insomnia questions. In the Davidson Trauma Scale, greater improvements were observed on irritability, difficulty concentrating, hyperstartle and a trend was observed on avoiding thoughts or feelings about the event. Greater improvements compared with placebo were noted on the Hamilton Depression (HAM-D) middle and late insomnia items. On the Hamilton Anxiety scale (HAM-A), the insomnia item was significantly improved. Conclusions: Quetiapine demonstrated greater effect than placebo on several symptoms. The strongest response was seen on insomnia, which the highest significance level on the CAPS. The insomnia items of both the HAM-D and HAM-A also demonstrated improvement with quetiapine. These finding indicate quetiapine improved sleep measure. Insomnia can be a difficult problem to treat in PTSD patients, therefore quetiapine should be considered in difficult cases.

Augmenting treatment efficiency in exposure therapy for PTSD: a randomized double-blind placebo-controlled trial of yohimbine HCl.

The alpha-2 adrenergic receptor antagonist, yohimbine, can facilitate fear extinction in animals and humans. One potential mechanism is increased noradrenergic activity and associated arousal in the presence of conditioned stimuli. Accordingly, yohimbine might augment prolonged exposure (PE) therapy for posttraumatic stress disorder (PTSD), where heightened exposure-oriented arousal is a theorized driver and empirical predictor of treatment success. A double-blind placebo-controlled randomized trial (NCT 01031979) piloted yohimbine augmentation in 26 males with combat-related PTSD. Participants were given one-time dose of yohimbine or placebo prior to the first imaginal exposure. Subsequently, both arms completed standard PE. The primary outcome was trauma-cued heart-rate reactivity a week after the drug/exposure visit, a highly specified, objective measure sensitive to incremental change. Secondary outcomes included arousal during the drug/exposure visit and slope of distress, PTSD, and depression over the course of PE. Consistent with hypothesis, yohimbine led to higher objective and subjective arousal during the drug/exposure visit and to lower trauma-cued heart-rate reactivity one-week later. One dose of yohimbine also led to greater between-session habituation and more rapid improvement on depression, but not PTSD, over the course of care. Results of this controlled pilot indicate support for continued investigation of yohimbine-augmented exposure therapy for PTSD.

Cue-dependent inhibition in posttraumatic stress disorder and attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are common among military veterans, but the comorbidity of these two psychiatric disorders remains largely unstudied. Evaluating response inhibition and cue-dependent learning as behavioral and neurocognitive mechanisms underlying ADHD/PTSD can inform etiological models and development of tailored interventions. METHOD: A cued go/no-go task evaluated response inhibition in 160 adult males. Participants were recruited from the community and a Veterans Administration medical center. Four diagnostic groups were identified: ADHD-only, PTSD-only, ADHD+PTSD, controls. RESULTS: Group differences were observed across most indices of inhibitory functioning, reaction time, and reaction time variability, whereby PTSD-only and ADHD+PTSD participants demonstrated deficits relative to controls. No cue dependency effects were observed. CONCLUSION: Finding complement prior work on neurocognitive mechanisms underlying ADHD, PTSD, and ADHD+PTSD. Lack of expected group differences for the ADHD-only group may be due to limited power. Additional work is needed to better characterize distinctions among clinical groups, as well as to test effects among women and youth.

A randomized controlled trial of ganaxolone in posttraumatic stress disorder.

Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3ß-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial ganaxolone group continued ganaxolone, while the placebo group crossed over to ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and ganaxolone was generally well tolerated. Trough blood levels of ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of ganaxolone to out-perform placebo. Future investigations of ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689.