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.

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.

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.

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.

Association Between Mental Health Burden and Coronary Artery Disease in U.S. Women Veterans Over 45: A National Cross-Sectional Study.

BACKGROUND: The women Veteran population accessing Veterans Health Administration (VA) care has grown rapidly. Women Veterans exhibit high rates of mental health conditions that increase coronary artery disease (CAD) risk; however, the relationship between specific conditions and increasing mental health burden to CAD in this population is unknown. MATERIALS AND METHODS: Using VA National Patient Care Data for 2009, we identified women Veterans over 45 (N = 157,195). Logistic regression models examined different mental health diagnoses and increasing mental health burden (number of diagnostic clusters) as predictors of CAD. RESULTS: CAD prevalence was 4.16%, and 36% of women Veterans were current smokers. Depression exhibited the strongest association with CAD (odds ratio [OR] 1.60, 95% confidence interval [CI] [1.50-1.71]), similar to that of current smoking (OR 1.68 [1.58-1.78]). Controlling for demographic variables, smoking, diabetes, and obesity, each additional mental health diagnosis increased the odds of CAD by 44%. CONCLUSIONS: Women Veterans over age 45 accessing VA care exhibited a high degree of mental health burden, which is associated with elevated odds of CAD; those with depression alone had 60% higher odds of CAD. For women Veterans using VA, mental health diagnoses may act as CAD risk factors that are potentially modifiable. Novel interventions in primary care and mental health are needed to address heart disease in this growing and aging population.

Neuroactive steroids and PTSD treatment.

This review highlights early efforts to translate pre-clinical and clinical findings regarding the role of neuroactive steroids in stress adaptation and PTSD into new therapeutics for PTSD. Numerous studies have demonstrated PTSD-related alterations in resting levels or the reactivity of neuroactive steroids and their targets. These studies also have demonstrated substantial variability in the dysfunction of specific neuroactive steroid systems among PTSD subpopulations. These variabilities have been related to the developmental timing of trauma, severity and type of trauma, genetic background, sex, reproductive state, lifestyle influences such as substance use and exercise, and the presence of comorbid conditions such as depression and chronic pain. Nevertheless, large naturalistic studies and a small placebo-controlled interventional study have revealed generally positive effects of glucocorticoid administration in preventing PTSD after trauma, possibly mediated by glucocorticoid receptor-mediated effects on other targets that impact PTSD risk, including other neuroactive steroid systems. In addition, clinical and preclinical studies show that administration of glucocorticoids, 17ß-estradiol, and GABAergic neuroactive steroids or agents that enhance their synthesis can facilitate extinction and extinction retention, depending on dose and timing of dose in relation to these complex PTSD-relevant recovery processes. This suggests that clinical trials designed to test neuroactive steroid therapeutics in PTSD may benefit from such considerations; typical continuous dosing regimens may not be optimal. In addition, validated and clinically accessible methods for identifying specific neuroactive steroid system abnormalities at the individual level are needed to optimize both clinical trial design and precision medicine based treatment targeting.

Deployment stress, tobacco use, and postdeployment posttraumatic stress disorder: Gender differences.

OBJECTIVE: Epidemiological research has demonstrated that tobacco use and posttraumatic stress disorder (PTSD) frequently co-occur and are highly prevalent among Veterans; research with female Veterans is limited. Given the increasing numbers of women deployed to combat zones in recent conflicts, the objective of the current study was to examine gender-specific associations between deployment stress, tobacco use and postdeployment PTSD symptoms. METHOD: Two thousand thirteen Veterans deployed to Afghanistan and Iraq (50.9% female; mean age = 35.53) completed a postdeployment, mailed survey that assessed tobacco use before, during, and after deployment, deployment stressors, and postdeployment PTSD symptoms. RESULTS: Warfare stress was associated with initiation and increases in tobacco use during deployment in both men and women, whereas harassment stress was associated with initiation and increases in tobacco use in women only. Only among women was continued postdeployment tobacco use associated with postdeployment PTSD symptoms. CONCLUSIONS: We found a dose-dependent relationship between deployment stress and adoption and escalation of tobacco use; the stressors that provoked initiation and escalation of tobacco use differed by gender. Continued tobacco use after deployment was associated with PTSD in women suggesting that women used tobacco more selectively than men to regulate negative affect. Implications of this work are that training before combat and during combat on healthy means of coping with deployment stress is needed to prevent tobacco use. For women, reducing harassment stress during deployment and early treatment of acute stress and PTSD during and soon after deployment may prevent intractable tobacco use.

Posttraumatic stress disorder and intimate partner violence in a women's headache center.

BACKGROUND: Posttraumatic stress disorder has been linked to women's ill health, including headaches. Intimate partner violence, which may result in posttraumatic stress disorder, is often reported by women with headaches. Prior studies of intimate partner violence and headache have estimated lifetime but not 12-month prevalence. The researchers in this study examined the relationship between headache and posttraumatic stress disorder in a novel population, and estimated 12-month and lifetime prevalence rates of intimate partner violence. METHODS: Patients were recruited from a women's headache center (n = 92) during 2006-07 and completed the Migraine Disability Assessment measure of headache severity. Posttraumatic stress disorder was measured using a modified Breslau scale. Twelve-month and lifetime physical intimate partner violence were measured with the Partner Violence Screen and the STaT ("slapped, threatened and throw") measure. Multivariable regression determined factors independently associated with headache severity. RESULTS: Among all participants, 28.3% screened positive for posttraumatic stress disorder; 9.8% and 36.9% of women endorsed recent and lifetime intimate partner violence. Posttraumatic stress disorder was strongly associated with headache severity (ß = 34.12, p = 0.01). Patients reporting lifetime intimate partner violence exhibited a trend of nine additional days of disability due to headache over 90 days. CONCLUSIONS: Posttraumatic stress disorder and intimate partner violence occur among a sizable proportion of women referred for headache. The authors' findings reaffirm that clinicians treating women with headaches must be aware of the possibility of posttraumatic stress disorder and intimate partner violence in such patients.