The Impact of the Menstrual Cycle and Underlying Hormones in Anxiety and PTSD: What Do We Know and Where Do We Go From Here?

PURPOSE OF REVIEW: This paper reviews the recent literature on menstrual cycle phase effects on outcomes relevant to anxiety and PTSD, discusses potential neurobiological mechanisms underlying these effects, and highlights methodological limitations impeding scientific advancement. RECENT FINDINGS: The menstrual cycle and its underlying hormones impact symptom expression among women with anxiety and PTSD, as well as psychophysiological and biological processes relevant to anxiety and PTSD. The most consistent findings are retrospective self-report of premenstrual exacerbation of anxiety symptoms and the protective effect of estradiol on recall of extinction learning among healthy women. Lack of rigorous methodology for assessing menstrual cycle phase and inconsistent menstrual cycle phase definitions likely contribute to other conflicting results. Further investigations that address these limitations and integrate complex interactions between menstrual cycle phase-related hormones, genetics, and psychological vulnerabilities are needed to inform personalized prevention and intervention efforts for women.

Neurotransmitter, Peptide, and Steroid Hormone Abnormalities in PTSD: Biological Endophenotypes Relevant to Treatment.

PURPOSE OF REVIEW: This review summarizes neurotransmitter, peptide, and other neurohormone abnormalities associated with posttraumatic stress disorder (PTSD) and relevant to development of precision medicine therapeutics for PTSD. RECENT FINDINGS: As the number of molecular abnormalities associated with PTSD across a variety of subpopulations continues to grow, it becomes clear that no single abnormality characterizes all individuals with PTSD. Instead, individually variable points of molecular dysfunction occur within several different stress-responsive systems that interact to produce the clinical PTSD phenotype. Future work should focus on critical interactions among the systems that influence PTSD risk, severity, chronicity, comorbidity, and response to treatment. Effort also should be directed toward development of clinical procedures by which points of molecular dysfunction within these systems can be identified in individual patients. Some molecular abnormalities are more common than others and may serve as subpopulation biological endophenotypes for targeting of currently available and novel treatments.

Biological studies of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular and molecular levels. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.

The influence of the menstrual cycle on reactivity to a CO2 challenge among women with and without premenstrual symptoms.

Clinically significant premenstrual symptoms (PMS) is conceptualized as a depressive disorder in DSM-5, however, it may share pathophysiological processes with anxiety- and fear-related disorders. Specifically, women with PMS panic at higher rates during biological challenge procedures. It is unclear if this increased interoceptive sensitivity is a general vulnerability or specific to the premenstrual phase. The current study examined the role of menstrual cycle phase on reactivity to a CO2 challenge among women with (n = 11) and without (n = 26) clinically significant PMS (N = 37). During the late follicular phase (days 6-12), women with and without PMS responded similarly to the CO2 challenge, whereas during the premenstrual phase (within 5 days before menses), women with PMS reported significantly more intense panic symptoms in response to the challenge than women without PMS. Vulnerability to panic in women with PMS may be specific to the premenstrual phase. Potential psychological and neurobiological mechanisms underlying this phenomenon are discussed.

PSYCHOTHERAPY VERSUS PHARMACOTHERAPY FOR POSTTRAUMATIC STRESS DISORDER: SYSTEMIC REVIEW AND META-ANALYSES TO DETERMINE FIRST-LINE TREATMENTS.

BACKGROUND: Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first-line treatment. Direct head-to-head comparisons are lacking. METHODS: Systemic review of Medline, EMBASE, PILOTS, Cochrane Central Register of Controlled Trials, PsycINFO, and Global Health Library was conducted without language restrictions. Randomized clinical trials ≥8 weeks in duration using structured clinical interview-based outcome measures, active-control conditions (e.g. supportive psychotherapy), and intent-to-treat analysis were selected for analyses. Independent review, data abstraction, and bias assessment were performed using standardized processes. Study outcomes were grouped around conventional follow-up time periods (3, 6, and 9 months). Combined effect sizes were computed using meta-analyses for medication versus control, medication pre-/posttreatment, psychotherapy versus control, and psychotherapy pre-/posttreatment. RESULTS: Effect sizes for trauma-focused psychotherapies (TFPs) versus active control conditions were greater than medications versus placebo and other psychotherapies versus active controls. TFPs resulted in greater sustained benefit over time than medications. Sertraline, venlafaxine, and nefazodone outperformed other medications, although potential for methodological biases were high. Improvement following paroxetine and fluoxetine treatment was small. Venlafaxine and stress inoculation training (SIT) demonstrated large initial effects that decreased over time. Bupropion, citalopram, divalproex, mirtazapine, tiagabine, and topiramate failed to differentiate from placebo. Aripiprazole, divalproex, guanfacine, and olanzapine failed to differentiate from placebo when combined with an antidepressant. CONCLUSIONS: Study findings support use of TFPs over nontrauma-focused psychotherapy or medication as first-line interventions. Second-line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment-as-usual conditions. Direct head-to-head trials of TFPs versus sertraline or venlafaxine are needed.

Menstrual cycle effects on psychological symptoms in women with PTSD.

The menstrual cycle has been implicated as a sex-specific biological process influencing psychological symptoms across a variety of disorders. Limited research exists regarding the role of the menstrual cycle in psychological symptoms among women with posttraumatic stress disorder (PTSD). The current study examined the severity of a broad range of psychological symptoms in both the early follicular (Days 2-6) and midluteal (6-10 days postlutenizing hormone surge) phases of the menstrual cycle in a sample of trauma-exposed women with and without PTSD (N = 49). In the sample overall, total psychological symptoms (d = 0.63), as well as depression (d = 0.81) and phobic anxiety (d = 0.81) symptoms, specifically, were increased in the early follicular compared to midluteal phase. The impact of menstrual cycle phase on phobic anxiety was modified by a significant PTSD × Menstrual Phase interaction (d = 0.63). Women with PTSD reported more severe phobic anxiety during the early follicular versus midluteal phase, whereas phobic anxiety did not differ across the menstrual cycle in women without PTSD. Thus, the menstrual cycle appears to impact fear-related symptoms in women with PTSD. The clinical implications of the findings and future research directions are discussed.

A genome-wide association study of clinical symptoms of dissociation in a trauma-exposed sample.

BACKGROUND: Recent work suggests that a subset of individuals with posttraumatic stress disorder (PTSD) exhibit marked dissociative symptoms, as defined by derealization and depersonalization. A dissociative subtype of PTSD was added to the diagnostic criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5) to capture this presentation of PTSD. This study examined genetic polymorphisms for association with the symptoms that define the dissociative subtype of PTSD using a genome-wide approach. METHODS: The sample comprised 484 White, non-Hispanic, trauma-exposed veterans and their partners who were assessed for lifetime PTSD and dissociation using a structured clinical interview. The prevalence of PTSD was 60.5%. Single-nucleotide polymorphisms (SNPs) from across the genome were obtained from a 2.5 million SNP array. RESULTS: Ten SNPs evidenced suggestive association with dissociation (P < 10(-5)). No SNPs met genome-wide significance criteria (P < 5 × 10(-8)). The peak SNP was rs263232 (ß = 1.4, P = 6.12 × 10(-7)), located in the adenylyl cyclase 8 (ADCY8) gene; a second SNP in the suggestive range was rs71534169 (ß = 1.63, P = 3.79 × 10(-6)), located in the dipeptidyl-peptidase 6 (DPP6) gene. CONCLUSIONS: ADCY8 is integral for long-term potentiation and synaptic plasticity and is implicated in fear-related learning and memory and long-term memory consolidation. DPP6 is critical for synaptic integration and excitation. These genes may exert effects on basic sensory integration and cognitive processes that underlie dissociative phenomena.

Tobacco withdrawal-induced changes in sensorimotor filtering as a predictor of smoking lapse in trauma-exposed individuals.

Prepulse inhibition (PPI) is a measure of sensorimotor filtering thought to shield the processing of initial weaker auditory stimuli from interruption by a later startle response. Previous studies have shown smoking withdrawal to have a negative impact on sensorimotor filtering, particularly in individuals with psychopathology. Because tobacco use may alleviate sensory and sensorimotor filtering deficits, we examined whether smoking withdrawal-induced changes in PPI were associated with maintenance of smoking abstinence in trauma-exposed individuals with and without PTSD who were attempting to quit smoking. Thirty-eight individuals (n = 24 with current or past PTSD; 14 trauma-exposed healthy controls) made an acute biochemically-verified smoking cessation attempt supported by 8 days of contingency management (CM) and cognitive behavioral therapy (CBT) for smoking. Participants completed a PPI task at the pre-quit baseline, 2 days post-quit, and 5 days post-quit. Post-quit changes in PPI were compared between those who remained abstinent for the first 8-days of the quit attempt and those who lapsed back to smoking. PPI changes induced by biochemically-verified smoking abstinence were associated with maintenance of abstinence across the 8-day CM/CBT-supported quit attempt. As compared to those who maintained tobacco abstinence, participants who lapsed to smoking had significantly lower PPI at 2 and 5 days post-quit relative to baseline. Thus, among trauma-exposed individuals, decreases in PPI during acute smoking cessation supported by CM/CBT are associated with lapse back to smoking. Interventions that improve PPI during early smoking abstinence may facilitate smoking cessation among such individuals who are at high risk for chronic, refractory tobacco use.

PTSD modifies performance on a task of affective executive control among deployed OEF/OIF veterans with mild traumatic brain injury.

Individuals with post-traumatic stress disorder (PTSD) show a cognitive bias for threatening information, reflecting dysregulated executive control for affective stimuli. This study examined whether comorbid mild Traumatic Brain Injury (mTBI) with PTSD exacerbates this bias. A computer-administered Affective Go/No-Go task measured reaction times (RTs) and errors of omission and commission to words with a non-combat-related positive or negative valence in 72 deployed United States service members from the wars in Iraq and Afghanistan. Incidents of military-related mTBI were measured with the Boston Assessment of Traumatic Brain Injury-Lifetime. PTSD symptoms were measured with the Clinician-Administered PTSD Scale. Participants were divided into those with (mTBI+, n = 34) and without a history of military-related mTBI (mTBI-, n = 38). Valence of the target stimuli differentially impacted errors of commission and decision bias (criterion) in the mTBI+ and mTBI- groups. Specifically, within the mTBI+ group, increasing severity of PTSD symptoms was associated with an increasingly liberal response pattern (defined as more commission errors to negative distractors and greater hit rate for positive stimuli) in the positive compared to the negative blocks. This association was not observed in the mTBI- group. This study underscores the importance of considering the impact of a military-related mTBI and PTSD severity upon affective executive control.

A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder.

Trauma-focused psychotherapies show general efficacy in post-traumatic stress disorder (PTSD), although outcomes vary substantially among individuals with PTSD and many patients do not achieve clinically meaningful symptom improvement. Several factors may contribute to poor treatment response, including genetic or environmental (e.g., stress) effects on neurobiological factors involved in learning and memory processes critical to PTSD recovery. In this review, we discuss the relationship between deficient GABAergic neurosteroid metabolites of progesterone, allopregnanolone (Allo) and pregnanolone (PA), and PTSD symptoms in men and women or PTSD-like behavioral abnormalities observed in male rodent models of PTSD. We also review the role and molecular underpinnings of learning and memory processes relevant to PTSD recovery, including extinction, extinction retention, reconsolidation of reactivated aversive memories and episodic non-aversive memory. We then discuss preclinical and clinical research that supports a role in these learning and memory processes for GABAergic neurosteroids and sulfated metabolites of Allo and PA that allosterically antagonize NMDA receptor function. Studies supporting the possible therapeutic impact of appropriately timed, acutely administered Allo or Allo analogs to facilitate extinction retention and/or block reconsolidation of aversive memories are also reviewed. Finally, we discuss important future directions for research in this area. Examining the varied and composite effects in PTSD of these metabolites of progesterone, as well as neuroactive derivatives of other parent steroids produced in the brain and the periphery, will likely enable a broadening of targets for treatment development. Defining contributions of these neuroactive steroids to common PTSD-comorbid psychiatric and medical conditions, as well as subpopulation-specific underlying dysfunctional physiological processes such as hypothalamic-pituitary-adrenal axis and immune system dysregulation, may also enable development of more effective multisystem precision medicines to prevent and treat the broader, polymorbid sequelae of extreme and chronic stress.

Pleiotropic endophenotypic and phenotype effects of GABAergic neurosteroid synthesis deficiency in posttraumatic stress disorder.

PTSD is associated with deficits in synthesis of progesterone metabolites such as allopregnanolone and pregnanolone that potently facilitate gamma-amino-butyric acid (GABA) effects at GABAA receptors. These neurosteroids modulate neuronal firing rate, regional brain connectivity, and activation of amygdala-mediated autonomic nervous system, hypothalamic-pituitary-adrenal axis, and behavioral reactions to unconditioned and conditioned threat. They also play critical roles in learning and memory processes such as extinction and extinction retention and inhibit toll-like receptor activation of intracellular pro-inflammatory pathways. Deficient synthesis of these neurosteroids thus may contribute to individually variable PTSD clinical phenotypes encompassing symptom severity, capacity for PTSD recovery, and vulnerability to common PTSD-comorbidities such as major depression, chronic pain, alcohol and nicotine dependence, cardiovascular disease, metabolic syndrome, reproductive disorders, and autoimmune conditions.

Plasma gamma-aminobutyric acid (GABA) levels and posttraumatic stress disorder symptoms in trauma-exposed women: a preliminary report.

RATIONALE: Aberrations in the stress response are associated with posttraumatic stress disorder (PTSD) symptom development, maintenance, and severity. Gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, may play a key role in stress recovery. OBJECTIVES: In this preliminary study, we examined whether plasma GABA levels differed between women with PTSD and trauma-exposed healthy controls. METHODS: Thirty participants provided plasma samples during two phases of the menstrual cycle: the early follicular phase and the mid-luteal phase. During each phase, blood was drawn after 45 min of rest, and after mild and moderately stressful psychophysiological tasks. Plasma GABA levels were measured using HPLC-mass spectrometry (LC-MS/MS). RESULTS: In analyses using PTSD diagnosis as a categorical group variable, women with and without a diagnosis of PTSD did not differ in plasma GABA levels (ps > .18). However, in analyses examining PTSD symptom severity as a continuous variable, there was a trend-level positive association between more severe PTSD symptoms and higher plasma GABA levels across the four blood draws (p = .06). In analyses examining DSM-IV PTSD symptom clusters separately, dysphoria symptoms were positively and significantly associated with plasma GABA levels (p = .03). Similarly, there was a trend-level positive association between avoidance cluster symptoms and plasma GABA levels (p = .06). Plasma GABA levels were not modulated by experimentally induced stress or menstrual cycle phase. CONCLUSIONS: Dysregulation in GABA may be a neurobiological marker and/or potential treatment target for women with PTSD symptom profiles characterized by prominent dysphoria and avoidance cluster symptoms.

Composite contributions of cerebrospinal fluid GABAergic neurosteroids, neuropeptide Y and interleukin-6 to PTSD symptom severity in men with PTSD.

Given that multiple neurobiological systems, as well as components within these systems are impacted by stress, and may interact in additive, compensatory and synergistic ways to promote or mitigate PTSD risk, severity, and recovery, we thought that it would be important to consider the collective, as well as separate effects of these neurobiological systems on PTSD risk. With this goal in mind, we conducted a proof-of-concept study utilizing cerebrospinal fluid (CSF) collected from unmedicated, tobacco- and illicit substance-free men with PTSD (n = 13) and trauma-exposed healthy controls (TC) (n = 17). Thirteen neurobiological factors thought to contribute to PTSD risk or severity based on previous studies were assayed. As the small but typical sample size of this lumbar puncture study limited the number of factors that could be considered in a hierarchical regression model, we included only those five factors with at least a moderate correlation (Spearman rho > 0.30) with total Clinician-Administered PTSD Scale (CAPS-IV) scores, and that did not violate multicollinearity criteria. Three of the five factors meeting these criteria-CSF allopregnanolone and pregnanolone (Allo + PA: equipotent GABAergic metabolites of progesterone), neuropeptide Y (NPY), and interleukin-6 (IL-6)-were found to account for over 75% of the variance in the CAPS-IV scores (R2 = 0.766, F = 8.75, p = 0.007). CSF Allo + PA levels were negatively associated with PTSD severity (ß = -0.523, p = 0.02) and accounted for 47% of the variance in CAPS-IV scores. CSF NPY was positively associated with PTSD severity (ß = 0.410, p = 0.04) and accounted for 14.7% of the CAPS-IV variance. There was a trend for a positive association between PTSD severity and CSF IL-6 levels, which accounted for 15.3% of the variance in PTSD severity (ß = 0.423, p = 0.05). Z-scores were then computed for each of the three predictive factors and used to depict the varying relative degrees to which each contributed to PTSD severity at the individual PTSD patient level. This first of its kind, proof-of-concept study bears replication in larger samples. However, it highlights the collective effects of dysregulated neurobiological systems on PTSD symptom severity and the heterogeneity of potential biological treatment targets across individual PTSD patients-thus supporting the need for precision medicine approaches to treatment development and prescribing in PTSD.

Moderated mediation for exercise maintenance in pain and posttraumatic stress disorder: A randomized trial.

This study utilizes the Science of Behavior Change (SOBC) experimental medicine approach to evaluate the effects of a 3-month, individually prescribed progressive exercise training program on neurobiological, cognitive and motivational mechanisms by which our exercise-training paradigm may foster exercise maintenance. We will investigate hypothesized relationships between exercise-training associated augmentation of neuropeptide Y (NPY) system function and improvements in self-regulation and reward sensitivity-cognitive control and motivational processes posited to promote self-efficacy and intrinsic motivation, which have been shown to predict exercise maintenance. This study will recruit Veterans with chronic low back pain and posttraumatic stress disorder (PTSD). Procedures include a baseline, acute cardiopulmonary exercise challenge assessment that will inform the exercise prescription for a 12-week progressive exercise training program comprised of three 45-minute aerobic exercise sessions per week-all of which will be supervised by an exercise physiologist. Additionally, a week-7 and week-14 exercise challenge assessment will track changes in NPY system function and the variables of interest. We hypothesize that increases in the capacity to release NPY in response to acute exercise testing will be associated with improvements in self-regulation and reward sensitivity, which will in turn be associated with self-efficacy and intrinsic motivation to maintain regular exercise. Ninety participants will be randomized either to the "active exercise training condition" or to the "wait list symptom monitoring condition". The study aims to demonstrate the feasibility of procedures and elucidate mechanisms relevant to developing individually prescribed, motivationally based exercise regimens to reduce negative consequences of PTSD and low back pain over the long-term. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Associations between PTSD-Related extinction retention deficits in women and plasma steroids that modulate brain GABAA and NMDA receptor activity.

Several studies have demonstrated poor retention of extinction learning among individuals with posttraumatic stress disorder (PTSD). Gonadal hormone signaling in brain appears to influence the retention of extinction learning differently in women with and without PTSD. Women with PTSD, compared to trauma-exposed women without PTSD, show relative deficits in extinction retention during the mid-luteal phase (mLP) of the menstrual cycle, compared to the early follicular phase (eFP). A PTSD-related reduction in conversion of progesterone to its GABAergic metabolites allopregnanolone (Allo) and pregnanolone (PA) may contribute to these findings. The current study in trauma-exposed women with (n = 9) and without (n = 9) PTSD investigated associations between extinction retention and plasma Allo + PA levels, as well as the ratio of Allo + PA to 5α-dihydroprogesterone (5α-DHP), the immediate steroid precursor for Allo. The study also investigated the relationship between extinction retention and the ratio of Allo + PA to dehydroepiandrosterone (DHEA), an adrenally-derived GABAA receptor antagonist. Study participants completed differential fear-conditioning during both the eFP and mLP of the menstrual cycle. Analyses revealed a strong positive relationship between resting plasma Allo + PA levels and extinction retention during the mLP in the women with, but not without, PTSD (e.g., diagnosis X Allo + PA interaction controlling for early extinction: ß = -.0008, p = .003). A similar pattern emerged for the Allo + PA to 5α-DHP ratio (ß = -.165, p = .071), consistent with a PTSD-related block in production of Allo and PA at the enzyme 3α-hydroxysteroid dehydrogenase. The ratio of Allo + PA to DHEA appeared to influence extinction retention only during the eFP when Allo + PA and DHEA levels are comparable and thus may compete for effects on GABAA receptor function. This study aligns with male rodent PTSD models linking experimental reductions in brain Allo levels to deficits in extinction retention and suggests that targeting PTSD-related deficits in GABAergic neurosteroid synthesis may be therapeutic.

The allopregnanolone to progesterone ratio across the menstrual cycle and in menopause.

The neuroactive steroid 3α-5α-tetrahydroprogesterone (allopregnanolone), a metabolite of progesterone, is a positive allosteric modulator of GABAA receptors, and low levels have been implicated in the etiology of mood disorders. However, it is not known whether metabolism of progesterone to allopregnanolone varies across the menstrual cycle or is low after menopause. We hypothesized that the allopregnanolone/progesterone ratio would decrease from the follicular to luteal phase. We also hypothesized that postmenopausal women would have lower levels of progesterone and allopregnanolone but similar allopregnanolone/progesterone ratios as premenopausal women in the follicular phase. Serum fasting allopregnanolone and progesterone levels were measured by gas chromatography-mass spectrometry in ten premenopausal women at the follicular, mid-cycle, and luteal phases of the menstrual cycle and in twenty-four postmenopausal women. Although allopregnanolone and progesterone levels increased from the follicular to luteal phase, the allopregnanolone/progesterone ratio decreased 8-fold [0.33 ± 0.08 (follicular) vs 0.16 ± 0.09 (mid-cycle) vs 0.04 ± 0.007 (luteal), p = 0.0003]. Mean allopregnanolone and progesterone levels were lower in postmenopausal than premenopausal women at all menstrual cycle phases (p < 0.01). The mean allopregnanolone/progesterone ratio was similar in postmenopausal and premenopausal women in the follicular phase (0.39 ± 0.08 vs 0.33 ± 0.08, p = 0.94) but was significantly lower at mid-cycle and in the luteal phase than in postmenopausal women (p < 0.01). In conclusion, the serum allopregnanolone/progesterone ratio decreases 8-fold from the follicular to luteal phase and is lower at mid-cycle and the luteal phase than in postmenopausal women. Whether these data have implications for luteal phase and other mood disorders merits further study.

Contingency management and cognitive behavioral therapy for trauma-exposed smokers with and without posttraumatic stress disorder.

INTRODUCTION: Trauma-exposed individuals with and without posttraumatic stress disorder (PTSD) are more likely to smoke and less successful in quit attempts than individuals without psychopathology. Contingency management (CM) techniques (i.e., incentives for abstinence) have demonstrable efficacy for smoking cessation in some populations with psychopathology, but have not been well tested in PTSD. This pilot study examined the feasibility of CM plus brief cognitive behavioral therapy (CBT) in promoting smoking cessation among trauma-exposed individuals with and without PTSD. METHODS: Fifty trauma-exposed smokers (18 with PTSD) were asked to abstain from tobacco and nicotine replacement therapy for one month. During week one of cessation, CBT was provided daily and increasing CM stipends were paid for each continuous day of biochemically-verified abstinence; CM stipends were withheld in response to smoking lapses and reset to the initial payment level upon abstinence resumption. CBT and fixed payments for study visits were provided during the subsequent three weeks. RESULTS: Of the 50 eligible participants who attended at least one pre-quit visit (49% female, 35% current PTSD), 43 (86%) attended the first post-quit study visit, 32 (64%) completed the first week of CM/CBT treatment, and 26 (52%) completed the study. Post-quit seven-day point prevalence abstinence rates for participants with and without PTSD, respectively, were similar: 39% vs. 38% (1 week), 33% vs. 28% (2 weeks), 22% vs. 19% (3 weeks), and 22% vs. 13% (4 weeks). CONCLUSIONS: Use of CM + CBT to support tobacco abstinence is a promising intervention for trauma-exposed smokers with and without PTSD.

Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD.

Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of progesterone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABAA receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABAA receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatography-mass spectrometry (GC-MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5α-dihydroprogesterone (5α-DHP: immediate precursor for allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n = 13) and trauma-exposed healthy controls (n = 17) after an overnight fast. Individual CSF steroids were quantified separately by GC-MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (ρ=-0.74, p = 0.006) and CAPS-IV derived Simms dysphoria cluster (ρ=-0.71, p = 0.01) scores. The allo+pregnan to DHEA ratio also was negatively correlated with total CAPS (ρ=-0.74, p = 0.006) and dysphoria cluster (ρ=-0.79, p = 0.002) scores. A PTSD-related decrease in the 5α-DHP to progesterone ratio indicated a block in allopregnanolone synthesis at 5α-reductase. This study suggests that CSF allo + pregnan levels correlate negatively with PTSD and negative mood symptoms in both men and women, but that the enzyme blocks in synthesis of these neurosteroids may be sex-specific. Consideration of sex, PTSD severity, and function of 5α-reductase and 3α-HSD thus may enable better targeting of neurosteroid-based PTSD treatments.

Positron emission tomography of tau in Iraq and Afghanistan Veterans with blast neurotrauma.

Military personnel are often exposed to multiple instances of various types of head trauma. As a result, there has been increasing concern recently over identifying when head trauma has resulted in a brain injury and what, if any, long-term consequences those brain injuries may have. Efforts to develop equipment to protect soldiers from these long-term consequences will first require understanding the types of head trauma that are likely responsible. In this study, we sought to identify the types of head trauma most likely to lead to the deposition of tau, a protein identified as a likely indicator of long-term negative consequences of brain injury. To define the types of head trauma in a military population, we applied a factor analysis to interviews from a larger cohort of 428 Veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders. Three factors were identified: Blast Exposure, Symptom Duration, and Blunt Concussion. Sixteen male Veterans from this study and one additional male civilian (aged 25-69, mean 35.2 years) underwent simultaneous positron emission tomography/magnetic resonance imaging using a tracer that binds to tau protein, the ligand T807/AV-1451 (Flortaucipir). Standard uptake value ratios to the isthmus of the cingulate were calculated from a 20-minute time frame 70 min post-injection. We found that tracer uptake throughout the brain was associated with Blast Exposure factor beta weights, but not with either Symptom Duration or Blunt Concussion. Associations with uptake were located primarily in the cerebellar, occipital, inferior temporal and frontal regions. The data suggest that in this small, relatively young cohort of Veterans, elevated T807/AV-1451 uptake is associated with exposure to blast neurotrauma. These findings are unanticipated, as they do not match histopathological descriptions of tau pathology associated with head trauma. Continued work will be necessary to understand the nature of the regional T807/AV-1451 uptake and any associations with clinical symptoms.

Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone.

Allopregnanolone and pregnanolone-neurosteroids synthesized from progesterone in the brain, adrenal gland, ovary and testis-have been implicated in a range of neuropsychiatric conditions including seizure disorders, post-traumatic stress disorder, major depression, post-partum depression, pre-menstrual dysphoric disorder, chronic pain, Parkinson's disease, Alzheimer's disease, neurotrauma, and stroke. Allopregnanolone and pregnanolone equipotently facilitate the effects of gamma-amino-butyric acid (GABA) at GABAA receptors, and when sulfated, antagonize N-methyl-D-aspartate receptors. They play myriad roles in neurophysiological homeostasis and adaptation to stress while exerting anxiolytic, antidepressant, anti-nociceptive, anticonvulsant, anti-inflammatory, sleep promoting, memory stabilizing, neuroprotective, pro-myelinating, and neurogenic effects. Given that these neurosteroids are synthesized de novo on demand, this review details the molecular steps involved in the biochemical conversion of cholesterol to allopregnanolone and pregnanolone within steroidogenic cells. Although much is known about the early steps in neurosteroidogenesis, less is known about transcriptional, translational, and post-translational processes in allopregnanolone- and pregnanolone-specific synthesis. Further research to elucidate these mechanisms as well as to optimize the timing and dose of interventions aimed at altering the synthesis or levels of these neurosteroids is much needed. This should include the development of novel therapeutics for the many neuropsychiatric conditions to which dysregulation of these neurosteroids contributes.