The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Does Symptom-Onset Treatment With Sertraline Improve Functional Impairment for Individuals With Premenstrual Dysphoric Disorder?: A Randomized Controlled Trial.

PURPOSE/BACKGROUND: Daily treatment with sertraline improves functional impairment among individuals with premenstrual dysphoric disorder (PMDD). We do not know whether treatment initiated at symptom onset also improves functional impairment. METHODS/PROCEDURES: This 3-site, double blind, randomized, clinical trial compared sertraline (25-100 mg) to similar appearing placebo, both administered at symptom onset, for reduction of PMDD symptoms. Ninety participants were allocated to sertraline and 94 participants to placebo. Functional outcomes from the Daily Ratings of the Severity of Problems included (1) reduced productivity or efficiency at work, school, home, or daily routine; (2) interference with hobbies or social activities; and (3) interference with relationships. Items were measured from 1 (no interference) to 6 (extreme interference) and averaged for the final 5 luteal phase days. This secondary analysis examined whether improvement in functional domains was greater for those allocated to sertraline compared with placebo. Second, we used causal mediation analyses to explore whether specific PMDD symptoms mediated functional improvement. RESULTS/FINDINGS: Only relationship functioning improved significantly with active treatment between baseline and the end of the second cycle (active group mean [SD] change, -1.39 [1.38]; placebo group mean change, -0.76 [1.20]; ß = -0.40; SE, 0.15; P = 0.009). The total effect of treatment on interference was -0.37 (95% confidence interval [CI], -0.66 to -0.09; P = 0.011). Given the nonsignificant direct effect (0.11; 95% CI, -0.07 to 0.29; P = 0.24) and significant indirect effect (-0.48; 95% CI, -0.71 to -0.24; P < 0.001), amelioration of anger/irritability likely mediated reductions in relationship interference. IMPLICATIONS/CONCLUSIONS: That anger/irritability mediates impairments in relationship functioning has face validity but should be replicated in other data sets. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00536198 .

Impact of duloxetine on male fertility: A randomised controlled clinical trial.

This study assessed the impact of duloxetine (serotonin and norepinephrine reuptake inhibitor) on semen parameters, sperm DNA fragmentation and serum hormones. We performed a double-blind, placebo-controlled, randomised clinical trial of duloxetine 60mg or placebo daily for 6 weeks (5 weeks full dose and 1 week taper). The primary outcome was the proportion of men with abnormal DNA fragmentation during and after duloxetine administration. Secondary outcomes were changes in semen parameters and hormones on treatment (2 and 6 weeks) and after discontinuation (8 and 10 weeks). Sixty-eight healthy males aged 18-65 were included. Duloxetine was not associated with an increase in the proportion of participants with abnormal sperm DNA fragmentation terminal deoxynucleotidyl transferase dUTP nick-end labelling scores (>25%) on treatment (p = 0.09) or after treatment (p = 0.56), nor did median sperm DNA fragmentation increase on treatment. Compared with placebo, there were no changes in bulk semen parameters during treatment. Limited changes in hormonal values were detected. This first published human study of a serotonin and norepinephrine reuptake inhibitor on male fertility revealed no clinically meaningful effects on sperm DNA fragmentation, semen parameters or serum hormones. Duloxetine, and possibly other serotonin and norepinephrine reuptake inhibitors, may be considered for men desiring fertility who require antidepressant treatment.

The bed nucleus of the stria terminalis and functionally linked neurocircuitry modulate emotion processing and HPA axis dysfunction in posttraumatic stress disorder.

BACKGROUND: The bed nucleus of the stria terminalis (BNST) plays an important role in rodent posttraumatic stress disorder (PTSD), but evidence to support its relevance to human PTSD is limited. We sought to understand the role of the BNST in human PTSD via fMRI, behavioral, and physiological measurements. METHODS: 29 patients with PTSD (childhood sexual abuse) and 23 healthy controls (HC) underwent BOLD imaging with an emotional word paradigm. Symptom severity was assessed using the Clinician-Administered PTSD Scale and HPA-axis dysfunction was assessed by measuring the diurnal cortisol amplitude index (DCAI). A data-driven multivariate analysis was used to determine BNST task-based functional co-occurrence (tbFC) across individuals. RESULTS: In the trauma-versus-neutral word contrast, patients showed increased activation compared to HC in the BNST, medial prefrontal cortex (mPFC), posterior cingulate gyrus (PCG), caudate heads, and midbrain, and decreased activation in dorsolateral prefrontal cortex (DLPFC). Symptom severity positively correlated with activity in the BNST, caudate head, amygdala, hippocampus, dorsal anterior cingulate gyrus (dACG), and PCG, and negatively with activity in the medial orbiotofrontal cortex (mOFC) and DLPFC. Patients and HC showed marked differences in the relationship between the DCAI and BOLD activity in the BNST, septal nuclei, dACG, and PCG. Patients showed stronger tbFC between the BNST and closely linked limbic and subcortical regions, and a loss of negative tbFC between the BNST and DLPFC. CONCLUSIONS: Based upon novel data, we present a new model of dysexecutive emotion processing and HPA-axis dysfunction in human PTSD that incorporates the role of the BNST and functionally linked neurocircuitry.

Predictors of involuntary and voluntary emotional episodic memories of virtual reality scenarios in Veterans with and without PTSD.

This study investigated predictors of involuntary and voluntary memories of stressful virtual reality scenarios. Thirty-two veterans of the two Persian Gulf Wars completed verbal memory tests and diagnostic assessments. They were randomly assigned to a Recounting (16) or a Suppression (16) condition. After immersion in the VR scenarios, the Recounting group described the scenarios and the Suppression group suppressed thoughts of the scenarios. One week later, participants completed surprise voluntary memory tests and another thought suppression task. The best predictors of voluntary memory were verbal memory ability, dissociation, and to a lesser extent, physiological arousal before and after scenarios. Dissociation and physiological stress responses selectively affected memory for neutral elements. Higher distress during scenarios impaired voluntary memory but increased the frequency of involuntary memories. Physiological stress responses promoted more frequent involuntary memories immediately after the scenarios. More frequent initial involuntary memories, tonic physiological arousal, and stronger emotional responses to dangerous events predicted difficulty inhibiting involuntary memories at follow-up. The effects of thought suppression were transient and weaker than those of other variables. The findings suggest that posttraumatic amnesia and involuntary memories of adverse events are more related to memory ability and emotional and physiological stress responses than to post-exposure suppression.

Severe Maternal Morbidity Among a Cohort of Post-9/11 Women Veterans.

Background: Maternal morbidity and mortality are key indicators of women's health status and quality of care. Maternal morbidity and mortality are high and rising in the United States. There has been no evaluation of severe maternal morbidity and mortality among veteran women, although population characteristics suggest that they may be at risk. This study aimed to evaluate a surveillance methodology at the U.S. Department of Veterans Affairs (VA) and describe the characteristics of women veterans who experienced severe maternal morbidity events. Materials and Methods: The study sample derived from a national sample of Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans who were enrolled for care at the VA. The surveillance methodology followed a recommended process of case identification and chart review following a standardized guide. Centers for Disease Control and Prevention (CDC) International Classification of Diseases codes for maternal morbidity were applied to billing, inpatient, and outpatient data for 9,829 pregnancies among 91,061 veteran women between January 1, 2014 and December 31, 2016. Descriptive statistics is reported. Results: One hundred twenty-seven pregnancies with severe maternal morbidity events were identified, 66 of which were confirmed after chart review. The positive predictive value of CDC indicators to identify cases was 0.52. High rates of mental health problems, obesity, rurality, maternal conditions, and racial discrepancies were noted among veterans who experienced severe maternal morbidity events. Conclusions: Severe maternal morbidity affects a significant number of veteran women. Systematic reporting of pregnancy outcomes and a multidisciplinary review committee would improve surveillance and case management at the VA. The VA is uniquely positioned to develop innovative comanagement strategies, especially in the area of perinatal mental health.

Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis.

The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this "declining effect". We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/).

Neuroendocrine Networks and Functionality.

Women undergo developmental and cyclic changes in hormonal exposures that affect brain function and mental health. Some women are more vulnerable to the effects of these hormonal exposures, for reasons that remain to be determined. Evidence to date indicates that anxiety and mood disorders are the most sensitive to hormonal fluctuations in women but there is also growing evidence for a protective effect of female reproductive hormones on schizophrenia. The hormonal exposures of the menstrual cycle, pregnancy, the postpartum period, lactation, and menopause are quite different and may be associated with at least partially distinct symptom profiles.

The relationship between posttraumatic and depressive symptoms during virtual reality exposure therapy with a cognitive enhancer.

Two studies suggest that reductions in posttraumatic symptoms (Aderka et al., 2013) and cognitions (Zalta et al., 2014) precede reductions in depressive symptoms during prolonged exposure (PE) therapy for posttraumatic stress disorder (PTSD) in female assault survivors. The present study explored the temporal relationship between posttraumatic and depressive symptoms in a randomized trial of D-Cycloserine (DCS) versus placebo augmented virtual reality exposure (VRE) therapy for chronic World Trade Center-related PTSD following the September 11, 2001 terrorist attacks. Twenty-five male and female participants were randomly assigned to receive either 100 mg DCS (N = 13) or placebo (N = 12) 90 min before 12 weekly VRE sessions. Participants contributed a total of 280 weekly PTSD Checklist (PCL; Weathers et al., 1993) and Beck Depression Inventory-second edition (BDI-II; Beck et al., 1996) symptom scores. Two sets of mediation analyses for longitudinal mixed models assessed the effects of 1) lagged PCL on BDI-II (Model 1), and 2) lagged BDI-II on PCL (Model 2) in the VRE-DCS and VRE-Placebo treatment groups, respectively. Results revealed reciprocal relations between posttraumatic and depressive symptoms during VRE treatment, although reductions in posttraumatic symptoms led to subsequent reductions in depressive symptoms to a greater extent than the converse. These effects were stronger in the DCS-enhanced group. Findings suggest that VRE primarily decreases posttraumatic symptoms, which in turn leads to decreased depressive symptoms, and that DCS may strengthen these effects.

Heart rate variability in alcohol use: A review.

BACKGROUND: Prior studies have shown that resting heart rate variability (HRV) is reduced in those with alcohol use disorders (AUD). However, HRV following an acute stressful stimulus (reactive HRV), and the relationship between resting or reactive HRV and drinking, craving and relapse in AUD have received less attention. METHODS: Studies using HRV in relationship to acute or chronic alcohol consumption were included in this review. Manuscripts that related to alcohol in the context of cardiovascular disease were excluded. RESULTS: Thirty-three articles were included and findings are presented in healthy social drinkers, moderate/heavy drinkers without AUD and individuals with AUD. Results on resting and reactive HRV were presented separately. Acute alcohol reduced resting HRV in healthy subjects but healthy controls had higher resting HRV then AUD subjects and moderate/heavy drinkers (in some studies). Resting HRV improved in AUD subjects only after at least 4 months of abstinence. AUD subjects had higher reactive HRV scores when compared to controls. In AUD subjects increased reactivity was related to more craving, faster relapse and more negative mood. Reactive HRV showed slower improvement with abstinence in AUD subjects. CONCLUSIONS: Chronic, heavy alcohol has a negative effect on the autonomic nervous system and may be a sensitive biomarker of craving and relapse.

Clinical phenotypes of perinatal depression and time of symptom onset: analysis of data from an international consortium.

BACKGROUND: The perinatal period is a time of high risk for onset of depressive disorders and is associated with substantial morbidity and mortality, including maternal suicide. Perinatal depression comprises a heterogeneous group of clinical subtypes, and further refinement is needed to improve treatment outcomes. We sought to empirically identify and describe clinically relevant phenotypic subtypes of perinatal depression, and further characterise subtypes by time of symptom onset within pregnancy and three post-partum periods. METHODS: Data were assembled from a subset of seven of 19 international sites in the Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium. In this analysis, the cohort was restricted to women aged 19-40 years with information about onset of depressive symptoms in the perinatal period and complete prospective data for the ten-item Edinburgh postnatal depression scale (EPDS). Principal components and common factor analysis were used to identify symptom dimensions in the EPDS. The National Institute of Mental Health research domain criteria functional constructs of negative valence and arousal were applied to the EPDS dimensions that reflect states of depressed mood, anhedonia, and anxiety. We used k-means clustering to identify subtypes of women sharing symptom patterns. Univariate and bivariate statistics were used to describe the subtypes. FINDINGS: Data for 663 women were included in these analyses. We found evidence for three underlying dimensions measured by the EPDS: depressed mood, anxiety, and anhedonia. On the basis of these dimensions, we identified five distinct subtypes of perinatal depression: severe anxious depression, moderate anxious depression, anxious anhedonia, pure anhedonia, and resolved depression. These subtypes have clear differences in symptom quality and time of onset. Anxiety and anhedonia emerged as prominent symptom dimensions with post-partum onset and were notably severe. INTERPRETATION: Our findings show that there might be different types and severity of perinatal depression with varying time of onset throughout pregnancy and post partum. These findings support the need for tailored treatments that improve outcomes for women with perinatal depression. FUNDING: Janssen Research & Development.

Neuroendocrine Networks and Functionality.

Women undergo developmental and cyclic changes in hormonal exposures that affect brain function and mental health. Some women are more vulnerable to the effects of these hormonal exposures, for reasons that remain to be determined. Evidence to date indicates that anxiety and mood disorders are the most sensitive to hormonal fluctuations in women but there is also growing evidence for a protective effect of female reproductive hormones on schizophrenia. The hormonal exposures of the menstrual cycle, pregnancy, the postpartum period, lactation, and menopause are quite different and may be associated with at least partially distinct symptom profiles.

D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data.

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

Pilot Study of a Telehealth-Delivered Medication-Augmented Exposure Therapy Protocol for PTSD.

Posttraumatic stress disorder (PTSD) is a serious condition, with certain occupations at increased risk due to greater trauma exposure. These same individuals face multiple barriers to care. This study aimed to investigate the feasibility of conducting a research trial with exposure therapy delivered via videoconferencing. Eleven adults working in occupations at risk with PTSD enrolled and seven completed 12 to 15 sessions. Individuals were randomized to receive the cognitive enhancer D-cycloserine or placebo, and participants provided saliva samples for genetic analysis. Treatment completers demonstrated decreases in PTSD and depressive symptomatology (measured by CAPS [p < 0.001, d = 2.79] and BDI-II [p = 0.004, d = 0.92]). Participants reported high therapeutic alliance, treatment satisfaction, and telehealth satisfaction. There were no significant technical, medication, or safety issues, and no clinical emergencies. The results suggest that it may be feasible to conduct clinical research using telehealth for PTSD and to use telehealth to increase access to care.

The Influence of Cyclic Hormonal Contraception on Expression of Premenstrual Syndrome.

BACKGROUND: Some women who use cyclic hormonal contraception (CHC) suffer from premenstrual symptoms; whether their symptoms differ from women who do not use CHC is not clear. OBJECTIVE: To compare women who use or do not use CHC on perimenstrual symptom timing and change severity. STUDY DESIGN: We analyzed daily symptom ratings from women who requested participation in (Screened Cohort: 103 used CHC and 387 did not) or were randomized in (Randomized Cohort: 41 used CHC and 211 did not) a clinical trial for premenstrual syndrome. We used effect sizes to compute and compare change scores between cycle phases in four partially overlapping perimenstrual windows defined relative to day 1 of menses [(-6, -1), (-5, 1), (-4, 2), (-3, 3)]. Differences in magnitude of change and timing were estimated using linear mixed-effects models. RESULTS: Both cohorts showed a significant two-way interaction between CHC use and symptom change scores (p < 0.01) and a significant main effect of perimenstrual window (p < 0.0001). Overall menstrual cycle symptom change was greater for the nonhormonal contraception versus hormonal contraception group. In the Screened Cohort, change scores were greater in the nonhormonal group specifically for depression (p = 0.04); anger or irritability (p < 0.01); and physical symptoms (p < 0.01). Mean change scores increased as the window shifted forward toward menses for both cohorts with the largest effect size and greatest group difference for (-4, 2) interval. CONCLUSIONS: CHC slightly attenuates menstrual cycle symptom change. The (-4, 2) perimenstrual interval shows the largest change compared with postmenses.

Adult separation anxiety in treatment nonresponders with anxiety disorders: delineation of the syndrome and exploration of attachment-based psychotherapy and biomarkers.

Clinically significant separation anxiety [SA] has been identified as being common among patients who do not respond to psychiatric interventions, regardless of intervention type (pharmacological or psychotherapeutic), across anxiety and mood disorders. An attachment formation and maintenance domain has been proposed as contributing to anxiety disorders. We therefore directly determined prevalence of SA in a population of adult treatment non-responders suffering from primary anxiety. In these separation anxious nonresponders, we pilot-tested an SA-focused, attachment-based psychotherapy for anxiety, Panic-Focused Psychodynamic Psychotherapy-eXtended Range [PFPP-XR], and assessed whether hypothesized biomarkers of attachment were engaged. We studied separation anxiety [SA] in 46 adults (ages 23-70 [mean 43.9 (14.9)]) with clinically significant anxiety symptoms (Hamilton Anxiety Rating Scale [HARS]≥15), and reporting a history of past non-response to psychotherapy and/or medication treatments. Thirty-seven (80%) had clinically significant symptoms of separation anxiety (Structured Clinical Interview for Separation Anxiety Symptoms [SCI-SAS] score≥8). Five of these subjects completed an open clinical trial of Panic Focused Psychodynamic Psychotherapy eXtended Range [PFPP-XR], a 21-24 session, 12-week manualized attachment-focused anxiolytic psychodynamic psychotherapy for anxiety. Patients improved on "adult threshold" SCI-SAS (current separation anxiety) (p=.016), HARS (p=0.002), and global severity, assessed by the Clinical Global Impression Scale (p=.0006), at treatment termination. Salivary oxytocin levels decreased 67% after treatment (p=.12). There was no significant change in high or low frequency HRV after treatment, but change in high frequency HRV inversely correlated with treatment change in oxytocin (p<.02), and change in low frequency HRV was positively associated with change in oxytocin (p<.02). SA is surprisingly prevalent among non-responders to standard anti-anxiety treatments, and it may represent a novel transdiagnostic target for treatment intervention in this population. Anxiety and global function improved in a small trial of a brief, manualized, attachment-focused psychodynamic psychotherapy, potentially supporting the clinical relevance of attachment dysfunction in this sample. The large decrease in oxytocin levels with treatment, although not statistically significant in this very small sample, suggests the need for further study of oxytocin as a putative biomarker or mediator of SA response. These pilot data generate testable hypotheses supporting an attachment domain underlying treatment-resistant anxiety, and new treatment strategies.

Symptom-Onset Dosing of Sertraline for the Treatment of Premenstrual Dysphoric Disorder: A Randomized Clinical Trial.

IMPORTANCE: Serotonin reuptake inhibitors (SRIs) are efficacious treatments for premenstrual dysphoric disorder (PMDD) when given daily or for half of the menstrual cycle during the luteal phase. Preliminary studies suggest that SRI treatment can be shortened to the interval from symptom onset through the beginning of menses. OBJECTIVE: To determine the efficacy of symptom-onset dosing with the SRI sertraline hydrochloride for treatment of PMDD. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, placebo-controlled, multisite, parallel-group randomized clinical trial conducted September 1, 2007, to February 29, 2012, at 3 university medical centers. In all, 252 women with PMDD started treatment at symptom onset and continued until the first few days of menses for 6 menstrual cycles. Intent-to-treat analyses were performed February 28, 2014, through April 21, 2015. INTERVENTIONS: Placebo or sertraline hydrochloride, 50 to 100 mg/d, during the symptomatic interval. MAIN OUTCOMES AND MEASURES: Premenstrual Tension Scale (PMTS) score was the primary outcome measure (score range, 0-36; 36 indicates most severe score). Secondary outcome measures included the Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C) (score range, 0-84; 84 indicates most severe score), Daily Record of Severity of Problems (DRSP) (total and subscale scores; higher scores indicate most severe problems), Clinical Global Impression (CGI) scales (score range, 1-7; 7 indicates most severe symptoms and least improvement), and Michelson SSRI (Selective SRI) Withdrawal Symptoms Scale scores (range, 0-51; higher scores indicate more severe withdrawal symptoms). RESULTS: Among the participants, 125 with PMDD were randomized to sertraline, and 127 to placebo. At baseline the mean (SD) PMTS scores for sertaline and placebo were 22.3 (4.8) and 21.4 (4.5), respectively, which declined to 11.7 (6.8) and 12.0 (6.9), respectively; group mean difference, 1.88 (95% CI, 0.01-3.75; P = .06). The mean (SD) estimated difference in IDS-C scores between baseline (35.4 [10.7] for sertraline; 32.8 [10.4] for placebo) and the end point (15.3 [10.7] for sertraline; 17.8 [11.0] for placebo) favored the sertraline group by 5.14 (95% CI, 1.97-8.31) points (P = .02). Compared with the placebo group, those assigned to sertraline showed greater improvement on the total DRSP score (estimated mean difference, 1.09 [95% CI, 0.96-1.25] points; P = .02) and Anger/Irritability DRSP subscale score (1.22 [95% CI, 1.05-1.41] points; P < .01) and were more likely to respond to treatment (77 of 115 patients [67.0%] for sertraline and 65 of 124 [52.4%] for placebo; χ21 = 5.23; P = .02). The mean (SD) number of symptomatic days before treatment diminished over time (sertraline, -0.7 [3.4] days; placebo, -1.0 [3.2] days), with no group differences in symptomatic days or the Michelson SSRI Withdrawal Symptoms Scale. CONCLUSIONS AND RELEVANCE: Depending on the symptom scale, women with PMDD may or may not benefit from SRI treatment during the interval from the onset of premenstrual symptoms through the first few days of menses. Abrupt treatment cessation was not associated with discontinuation symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00536198.

Neurobiology of Maternal Stress: Role of Social Rank and Central Oxytocin in Hypothalamic-Pituitary Adrenal Axis Modulation.

BACKGROUND: Chronic stress may conceivably require plasticity of maternal physiology and behavior to cope with the conflicting primary demands of infant rearing and foraging for food. In addition, social rank may play a pivotal role in mandating divergent homeostatic adaptations in cohesive social groups. We examined cerebrospinal fluid (CSF) oxytocin (OT) levels and hypothalamic-pituitary adrenal (HPA) axis regulation in the context of maternal social stress and assessed the contribution of social rank to dyadic distance as reflective of distraction from normative maternal-infant interaction. METHODS: Twelve socially housed mother-infant bonnet macaque dyads were studied after variable foraging demand (VFD) exposure compared to 11 unstressed dyads. Dyadic distance was determined by behavioral observation. Social ranking was performed blindly by two observers. Post-VFD maternal plasma cortisol and CSF OT were compared to corresponding measures in non-VFD-exposed mothers. RESULTS: High-social rank was associated with increased dyadic distance only in VFD-exposed dyads and not in control dyads. In mothers unexposed to VFD, social rank was not related to maternal cortisol levels, whereas VFD-exposed dominant versus subordinate mothers exhibited increased plasma cortisol. Maternal CSF OT directly predicted maternal cortisol only in VFD-exposed mothers. CSF OT was higher in dominant versus subordinate mothers. VFD-exposed mothers with "high" cortisol specifically exhibited CSF OT elevations in comparison to control groups. CONCLUSION: Pairing of maternal social rank to dyadic distance in VFD presumably reduces maternal contingent responsivity, with ensuing long-term sequelae. VFD-exposure dichotomizes maternal HPA-axis response as a function of social rank with relatively reduced cortisol in subordinates. OT may serve as a homeostatic buffer during maternal stress exposure.

Pregnancy distress gets under fetal skin: Maternal ambulatory assessment & sex differences in prenatal development.

Prenatal maternal distress is associated with an at-risk developmental profile, yet there is little fetal evidence of this putative in utero process. Moreover, the biological transmission for these maternal effects remains uncertain. In a study of n = 125 pregnant adolescents (ages 14-19), ambulatory assessments of daily negative mood (anger, frustration, irritation, stress), physical activity, blood pressure, heart rate (every 30 min over 24 hr), and salivary cortisol (six samples) were collected at 13-16, 24-27, 34-37 gestational weeks. Corticotropin-releasing hormone, C-reactive protein, and interleukin 6 from blood draws and 20 min assessments of fetal heart rate (FHR) and movement were acquired at the latter two sessions. On average, fetuses showed development in the expected direction (decrease in FHR, increase in SD of FHR and in the correlation of movement and FHR ("coupling")). Maternal distress characteristics were associated with variations in the level and trajectory of fetal measures, and results often differed by sex. For males, greater maternal 1st and 2nd session negative mood and 2nd session physical activity were associated with lower overall FHR (p < .01), while 1st session cortisol was associated with a smaller increase in coupling (p < .01), and overall higher levels (p = .05)-findings suggesting accelerated development. For females, negative mood, cortisol, and diastolic blood pressure were associated with indications of relatively less advanced and accelerated outcomes. There were no associations between negative mood and biological variables. These data indicate that maternal psychobiological status influences fetal development, with females possibly more variously responsive to different exposures.