Acute analgesic effect of nicotine vaping using three experimental pain induction tasks: a randomized, placebo-controlled laboratory study.

RATIONALE: Pain and nicotine use are co-occurring conditions with a significant impact on health. Experimental evidence supports an acute analgesic effect of nicotine which may reinforce nicotine use among those with chronic pain. Evidence for nicotine analgesia have primarily been gathered in combustible cigarette users and have not been extended to electronic nicotine delivery systems (ENDS or vaping). Furthermore, the mechanisms of nicotine analgesia in humans are not well understood. OBJECTIVES: Assess the effect of acute vaped nicotine on subjective and behavioral indices of pain sensitivity using three tasks designed to probe distinct mechanisms of analgesia. METHODS: This study recruited ENDS users (N = 86) to undergo a paced vaping protocol followed by pain tasks in counterbalanced order. Across four sessions, participants vaped e-liquid containing nicotine or placebo, and flavor or no-flavor in a 2 × 2 within-subject design. Assessments included cold pressor, submaximal effort tourniquet to induce ischemic pain, and temporal summation of heat pain, an index of central sensitization. RESULTS: Compared to placebo, nicotine increased cold pressor pain tolerance (ηp2 = 0.031), ischemic pain threshold (ηp2 = 0.073) and tolerance (ηp2 = 0.056) but had no effect on temporal summation of pain. Flavor did not affect pain sensitivity. Females reported greater ischemic pain sensitivity (ηp2 = 0.027) and greater reductions in craving (ηp2 = 0.086). CONCLUSIONS: Consistent with research from tobacco smoking, analgesia may be reinforcing and contribute to nicotine dependence among ENDS users. More research on sex differences is warranted.

Is trait rumination associated with affective reactivity to the menstrual cycle? A prospective analysis.

BACKGROUND: A minority of naturally cycling individuals experience clinically significant affective changes across the menstrual cycle. However, few studies have examined cognitive and behavioral constructs that may maintain or worsen these changes. Several small studies link rumination with premenstrual negative affect, with authors concluding that a tendency to ruminate amplifies and perpetuates hormone-sensitive affective symptoms. Replication in larger samples is needed to confirm the validity of rumination as a treatment target. METHOD: 190 cycling individuals (M = 30.82 years; 61.1% Caucasian) were recruited for moderate perceived stress, a risk factor for cyclical symptoms. They completed the Rumination Response Scale at baseline, then reported daily affective and physical symptoms across 1-6 cycles. Multilevel growth models tested trait rumination as a predictor of baseline levels, luteal increases, and follicular decreases in symptoms. RESULTS: The degree of affective cyclicity was normally distributed across a substantial range, supporting feasibility of hypothesis tests and validating the concept of dimensional hormone sensitivity. Contrary to prediction, higher brooding did not predict levels or cyclical changes of any symptom. In a subsample selected for luteal increases in negative affect, brooding predicted higher baseline negative affect but still did not predict affective cyclicity. CONCLUSIONS: An individual's trait-like propensity to engage in rumination may not be a valid treatment target in premenstrual mood disorders. State-like changes in rumination should still be further explored, and well-powered prospective studies should explore other cognitive and behavioral factors to inform development of targeted psychological treatments for patients with cyclical affective symptoms.

Effects of Nicotine Content and Preferred Flavor on Subjective Responses to E-cigarettes: A Randomized, Placebo-controlled Laboratory Study.

INTRODUCTION: Evidence suggests that e-liquid flavor and nicotine concentration are important factors in the initiation and maintenance of e-cigarette use (vaping). Flavors may increase the initiation and maintenance of vaping, and nicotine content is a factor in e-cigarette dependence and the efficacy of e-cigarettes for cigarette smoking cessation. Few human laboratory studies have assessed the joint and interactive effects of flavor and nicotine on subjective responses to e-cigarettes. METHODS: Regular e-cigarette users (N = 89) completed a multi-session study involving a paced vaping procedure with e-liquid cartridges containing their preferred flavor (berry, menthol, or tobacco) or no flavor, with or without nicotine (18 mg). Subjective effects of vaping (satisfaction, reward, aversion, airway sensations, and craving relief) were assessed. RESULTS: Nicotine significantly increased psychological reward and craving relief, whereas flavor significantly increased vaping satisfaction and taste. Nicotine dependence severity moderated the effect of nicotine on reward, such that those with the greatest dependence severity reported the greatest reward. CONCLUSIONS: These findings support differential and noninteractive effects of e-liquid nicotine content and flavor on reinforcing effects of e-cigarettes. IMPLICATIONS: E-liquid flavor and nicotine content have independent, non-interactive effects on subjective responses to vaping under controlled laboratory conditions. Among regular e-cigarette users, vaping a preferred flavor increased taste and satisfaction, but did not interact with nicotine to alter reward or craving. Further research on the ways in which these subjective effects may motivate vaping behavior among different populations of e-cigarette users would be useful to inform regulatory policy of ENDS products.

Hormone sensitivity predicts the beneficial effects of transdermal estradiol on reward-seeking behaviors in perimenopausal women: A randomized controlled trial.

Depression is highly prevalent during the menopause transition (perimenopause), and often presents with anxious and anhedonic features. This increased vulnerability for mood symptoms is likely driven in part by the dramatic hormonal changes that are characteristic of the menopause transition, as prior research has linked fluctuations in estradiol (E2) to emergence of depressed mood in at risk perimenopausal women. Transdermal estradiol (TE2) has been shown to reduce the severity of depression in clinically symptomatic women, particularly in those with recent stressful life events. This research extends prior work by examining the relation between E2 and reward seeking behaviors, a precise behavioral indicator of depression. Specifically, the current study utilizes a randomized, double blind, placebo-controlled design to investigate whether mood sensitivity to E2 flux ("hormone sensitivity") predicts the beneficial effects of TE2 interventions on reward seeking behaviors in perimenopausal women, and whether recent stressful life events moderate any observed associations. METHOD: Participants were 66 women who met standardized criteria for being early or late perimenopausal based on bleeding patterns. Participants were recruited from a community sample; therefore, mood symptoms varied across the continuum and the majority of participants did not meet diagnostic criteria for a depressive or anxiety disorder at the time of enrollment. Hormone sensitivity was quantified over an 8-week baseline period, using within-subjects correlations between repeated weekly measures of E2 serum concentrations and weekly anxiety (State Trait Anxiety Inventory) and anhedonia ratings (Snaith-Hamilton Pleasure Scale). Women were then randomized to receive 8 weeks of TE2 (0.1 mg) or transdermal placebo, and reward-seeking behaviors were assessed using the Effort-Expenditure for Rewards Task (EEfRT). RESULTS: Participants who were randomized to receive transdermal estradiol and who demonstrated greater anxiety sensitivity to E2 fluctuations at baseline, demonstrated more reward seeking behaviors on the EEfRT task. Notably, the strength of the association between E2-anxiety sensitivity and post-randomization EEfRT for TE2 participants increased when women experienced more recent stressful life events and rated those events as more stressful. E2-anhedonia sensitivity was not associated with reward-seeking behaviors. CONCLUSION: Perimenopausal women who are more sensitive to E2 fluctuations and experienced more recent life stress may experience a greater benefit of TE2 as evidenced by an increase in reward seeking behaviors.

Cyclical exacerbation of suicidal ideation in female outpatients: Prospective evidence from daily ratings in a transdiagnostic sample.

Suicide is a leading cause of death among females of reproductive age. The menstrual cycle is a plausible yet understudied trigger for acute suicide risk. Cross-sectional studies have demonstrated a greater frequency of suicide attempts and deaths in the weeks before and after the onset of menses compared to other cycle phases. Here, using prospective daily ratings, we examine the relationship between the cycle and suicidal ideation (SI) and related symptoms known to show a cyclical change in some patients (depression, hopelessness, guilt, rejection sensitivity, interpersonal conflict, anxiety, mood swings, and anger/irritability). Thirty-eight naturally cycling outpatients recruited for past-month SI reported SI severity and other symptoms across an average of 40 days. Participants were excluded for hormone use, pregnancy, irregular cycles, serious medical illness, and body mass index > 29.9 or < 18. Intraclass correlations ranged from .29 to .46, highlighting that most symptom variance lies within-person. Cyclical worsening of symptoms was evaluated using phase contrasts in multilevel models. Most symptoms, including SI, were significantly worse in the perimenstrual phase than in all other phases. Additionally, anger/irritability was higher in the midluteal than in the midfollicular phase, and several symptoms of depression were higher in the midfollicular than in the periovulatory phase. Otherwise, symptoms did not significantly differ between the midluteal, midfollicular, and periovulatory phases. Cycle phase predictors accounted for 25% of the within-person variance in SI. Females with SI may be at risk for perimenstrual worsening of SI and related symptoms. These findings highlight the importance of assessing the cycle phase for improved prediction of suicide risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of acute estradiol and progesterone on perimenstrual exacerbation of suicidal ideation and related symptoms: a crossover randomized controlled trial.

Female suicide attempts peak peri-menstrually-around the onset of menses-when the ovarian steroids estradiol (E2) and progesterone (P4) fall rapidly. Given preclinical evidence that withdrawal from either E2 or P4 can provoke behaviors consistent with elevated suicide risk, we hypothesized that withdrawal from one or both of these steroids contributes to perimenstrual exacerbation of suicidal ideation (SI) and related symptoms. In a randomized, controlled, double-blind crossover experiment (NCT03720847), a transdiagnostic sample of naturally cycling, medically healthy psychiatric outpatients reporting past-month SI completed two conditions during two different 14-day experimental intervals (days 7-20 where the luteinizing hormone surge = day 0), separated by a monthlong washout cycle. In the E2 and P4 (EP) condition, participants received transdermal E2 (0.1 mg/day) plus oral micronized P4 (200 mg/day as 100 mg twice daily) to buffer perimenstrual steroid withdrawal. A matched placebo (PBO) condition allowed natural perimenstrual steroid withdrawal. Participants reported daily SI and planning (primary outcomes) and indices of depression (low mood, hopelessness), threat sensitivity (anxiety, perceived stress), executive functioning (difficulty concentrating, impulsivity), and social cognitive bias (rejection sensitivity, perceived burdensomeness). In baseline cycles, no participant met prospective criteria for DSM-5 premenstrual dysphoric disorder, but 59% met all criteria except full follicular symptom remission, and 93% showed the highest SI in the perimenstrual phase. Of 29 randomized, 28 were analyzed (14 EP-PBO, 14 PBO-EP). Experimental administration of E2 and P4 (relative to PBO) reduced perimenstrual exacerbation of SI, suicide planning, depression, hopelessness, perceived stress, rejection sensitivity, and perceived burdensomeness, particularly in the perimenstrual (natural E2 and P4 withdrawal) days. Further, delayed withdrawal from experimental E2 and P4 (but not PBO) recapitulated SI, hopelessness, and rejection sensitivity. Acute perimenstrual withdrawal from ovarian steroids may play a causal role in perimenstrual worsening of depression and SI.

Baseline anxiety-sensitivity to estradiol fluctuations predicts anxiety symptom response to transdermal estradiol treatment in perimenopausal women - A randomized clinical trial.

BACKGROUND: The menopausal transition (perimenopause) is associated with an increased risk of major depression, characterized by anxiety and anhedonia phenotypes. Greater estradiol (E2) variability predicts the development of perimenopausal depression, especially within the context of stressful life events (SLEs). While transdermal E2 (TE2) reduces perimenopausal depressive symptoms, the mechanisms underlying TE2 efficacy and predictors of TE2 treatment response remain unknown. This study aimed at determining relationships between E2 fluctuations, mood symptoms, and physiologic stress-reactivity (cortisol and interleukin-6) and whether differences in mood-sensitivity to E2 fluctuations predict mood responses to TE2 treatment. METHODS: This randomized, double-blind, placebo-controlled trial investigated medically healthy women (46-60 years) in the early or late menopause transition. Baseline E2-sensitivity strength was calculated from eight weekly individual correlations between week-to-week E2 change and index week anxiety (State-Trait Anxiety Inventory) and anhedonia (Snaith-Hamilton Pleasure Scale). Women then received eight weeks of TE2 or transdermal placebo. RESULTS: Analyses included 73 women (active TE2 n = 35). Greater baseline E2 fluctuations predicted greater anhedonia (p = .002), particularly in women with more SLEs. Greater E2 fluctuations also predicted higher cortisol (p = .012) and blunted interleukin-6 (p = .02) stress-responses. Controlling for baseline symptoms, TE2 was associated with lower post-treatment anxiety (p < .001) and anhedonia (p < .001) versus placebo. However, the efficacy of TE2 for anxiety (p = .007) and also for somatic complaints (p = .05) was strongest in women with greater baseline E2 sensitivity strength. CONCLUSIONS: TE2 treatment reduced perimenopausal anxiety and anhedonia. The ability of baseline mood-sensitivity to E2 fluctuations to predict greater TE2 efficacy has implications for individualized treatment of perimenopausal anxiety disorders.

Personal resource profiles of individuals with a history of interpersonal trauma and their impact on opioid misuse.

OBJECTIVE: Individuals who experience interpersonal trauma (e.g., intimate partner violence, sexual assault, and adverse childhood experiences) are disproportionately affected by the opioid epidemic; however, not all will engage in opioid misuse behaviors. Personal resources, such as coping, social support, and self-efficacy, may attenuate the negative effects of trauma and foster resiliency. This study examines how personal resources affect opioid misuse among individuals with a history of interpersonal trauma. METHOD: Data were collected from a convenience sample (N = 236) through a cross-sectional, self-report survey. Latent profile analysis identified subgroups with different personal resource profiles based on coping behaviors, social support, and health-related self-efficacy. Logistic regression examined subgroup differences in sociodemographics and opioid misuse behaviors. RESULTS: Results supported a 3-class (low, moderate, and high personal resource groups) and 4-class model (low, internal, external, and high resource groups). Males, African Americans, and Hispanics were more likely to have low resource profiles. Low resource groups had the highest probability of reporting opioid misuse; however, there were no significant between-class differences after adjusting for depressive symptoms, pain intensity, sex, race/ethnicity, and age. Pain intensity and depressive symptoms largely accounted for subgroup differences in opioid misuse. CONCLUSIONS: Findings suggest that sex and race/ethnicity play an important role in the personal resource profiles of individuals with a history of interpersonal trauma. Interventions to promote resiliency and mitigate the effects of trauma on opioid misuse should consider personal resource profiles, mental health, and effective pain management. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

How to study the menstrual cycle: Practical tools and recommendations.

Despite decades of research on the physiological and psychological effects of the menstrual cycle, studies have not sufficiently adopted consistent methods for operationalizing the menstrual cycle. This has resulted in substantial confusion in the literature and limited possibilities to conduct systematic reviews and meta-analyses. In order to facilitate more rapid accumulation of knowledge on cycle effects, the present paper offers a set of integrative guidelines and standardized tools for studying the menstrual cycle as an independent variable. We begin with (1) an overview of the menstrual cycle and (2) premenstrual disorders, followed by (3) recommendations and tools regarding data collection in cycle studies. These recommendations address selecting the appropriate study design and sampling strategy, managing demand characteristics, identifying a sample of naturally-cycling individuals, and measuring menstrual bleeding dates, ovarian hormones, and ovulation. We proceed with suggestions for (4) data preparation and coding of cycle day and phases, as well as (5) data visualization, statistical modeling, and interpretation of menstrual cycle associations. We also provide (6) recommendations for using menses start day and ovulation testing to schedule visits in laboratory studies and end with a (7) comprehensive summary and conclusion. Regardless of whether the influence of the menstrual cycle is of central interest in a study or should be controlled to accurately assess the effects of another variable, the use of these recommendations and tools will help make study results more meaningful and replicable.

Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors.

BACKGROUND: The cardiovascular (CV) safety of estrogen replacement therapy (ERT) in perimenopausal women remains uncertain. Although exogenous estrogens increase HDL cholesterol (HDL-C), estrogen-mediated effects on alternative metrics of HDL that may better predict CV risk are unknown. OBJECTIVE: To determine the effects of transdermal ERT on HDL composition and cholesterol efflux capacity (CEC), as well as the relationships between these metrics and CV risk factors. METHODS: Fasting plasma samples were analyzed from 101 healthy, perimenopausal women randomized to receive either transdermal placebo or transdermal estradiol (100 µg/24 h) with intermittent micronized progesterone. At baseline and after 6 months of treatment, serum HDL CEC, HDL particle concentration, HDL protein composition, insulin resistance and brachial artery flow-mediated dilatation (FMD) were measured. RESULTS: No difference between groups was found for change in plasma HDL-C (p = 0.69). Between-group differences were found for changes in serum HDL total CEC [median change from baseline -5.4 (-17.3,+8.4)% ERT group versus +5.8 (-6.3,+16.9)% placebo group, p = 0.01] and ABCA1-specific CEC [median change from baseline -5.3 (-10.7,+6.7)% ERT group versus +7.4 (-1.5,+18.1)% placebo group, p = 0.0002]. Relative to placebo, transdermal ERT led to reductions in LDL-C (p < 0.0001) and insulin resistance (p = 0.0002). An inverse correlation was found between changes in serum HDL total CEC and FMD (ß = -0.26, p = 0.004). CONCLUSIONS: Natural menopause leads to an increase in serum HDL CEC, an effect that is abrogated by transdermal ERT. However, transdermal ERT leads to favorable changes in major CV risk factors.

IL-6 Response to Psychosocial Stress Predicts 12-month Changes in Cardiometabolic Biomarkers in Perimenopausal Women.

OBJECTIVE: Cardiometabolic diseases are the number one cause of mortality, accounting for over one third of all deaths in the United States. Cardiometabolic risk further increases with psychosocial stress exposure and during menopausal transition in women. Because disease risk and stress burden are associated with aberrant immune signaling, we hypothesized that responses of interleukin-6 (IL-6) to psychosocial stress may predict longitudinal cardiometabolic outcomes in perimenopausal women. METHODS: We conducted post hoc analyses in 151 perimenopausal or early postmenopausal women participants in a previously completed study. At study onset, participants underwent the Trier Social Stress Test (TSST), and plasma IL-6 was measured repeatedly before and during the 1 hour post-TSST. Subsequently, participants were randomly assigned to either hormonal treatment (HT) or placebo and followed for 12 months to determine longitudinal changes in cardiometabolic biomarkers. RESULTS: Greater IL-6 reactivity to stress, measured with baseline-adjusted area under the curve, predicted 12-month decrease in flow-mediated dilatation of the brachial artery (P = 0.0005), a measure of endothelial-dependent vascular function, but not in endothelial-independent function measured with nitroglycerin-mediated dilatation (P = 0.17). Greater baseline IL-6 levels predicted 12-month increase in insulin resistance based on the homeostatic model assessment of insulin resistance score (P = 0.0045) and in the number of criteria met for metabolic syndrome (P = 0.0008). These predictions were not moderated by HT. CONCLUSIONS: Greater baseline IL-6 levels as well as its reactivity to stress may predict worsening in distinct cardiometabolic biomarkers as women transition to menopause. Interleukin-6 reactivity predicts decline in endothelial-dependent vascular function, whereas baseline IL-6 presages accumulation of metabolic risk.

The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease.

BACKGROUND: The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease. METHODS: Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day) + IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12. RESULTS: Of 172 women enrolled, those assigned to TE + IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE + IMP. Women on TE + IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing. CONCLUSIONS: TE + IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.

Effects of perimenopausal transdermal estradiol on self-reported sleep, independent of its effect on vasomotor symptom bother and depressive symptoms.

OBJECTIVE: The aim of this study was to determine the efficacy of transdermal estradiol (E2) plus intermittent progesterone (EPT) for improving self-reported sleep in perimenopausal women, after controlling for vasomotor symptoms (VMS) bother and depressive symptoms. METHODS: Using a double-blind, placebo-controlled design, 172 healthy women meeting STRAW+10 criteria for being in the menopausal transition or early postmenopause were randomized to 12 months of transdermal E2 (0.1 mg/d) + 200 mg progesterone (12 d every 3 mo) or placebo. Using standard questionnaires, self-reported sleep, depression, and VMS bother were obtained at baseline and bimonthly postrandomization. RESULTS: Controlling for baseline levels, EPT (vs placebo) led to reductions in minutes to fall asleep (estimate = -0.12, P = 0.002) and number of awakenings (estimate = -0.24, P = 0.04) over the 12 months. Controlling for changes in VMS bother and depressive symptoms, EPT still predicted reductions in minutes to fall asleep (estimate = -0.28, P = 0.02) and number of awakenings (estimate = -0.11, P = 0.02) over the 12 months. CONCLUSIONS: We extend existing research by demonstrating that hormone therapy (HT) in subjective sleep cannot be fully explained by improvements in VMS bother or depressive symptoms. Research to examine the mechanism (s) underlying HT's effects on sleep would have public health significance for perimenopausal women and also advance our general understanding of the pathophysiology of impaired sleep.

Ovarian hormones influence eating disorder symptom variability during the menopause transition: A pilot study.

OBJECTIVE: Eating disorder symptoms change in a predictable pattern over the menstrual cycle such that changes in symptoms are triggered by changes in the ovarian hormones estradiol (E2) and progesterone (P4). To date, work in this area has focused exclusively on young adult women. The objective of this pilot study was to examine the effect of E2 and P4 on eating disorder symptom change in midlife women during early perimenopause. METHOD: Participants included women aged 42-52 in early perimenopause (n=8). In-home self-assessments were completed for one menstrual cycle or 40-days, whichever occurred first. In-home self-assessments included collecting saliva samples each morning for E2 and P4 assays and completing online study questionnaires at the end of each day. Multilevel regression models examined the associations of E2 and P4 with daily symptoms of binge eating and body dissatisfaction. RESULTS: E2 was positively associated with binge eating when P4 was high, but not when P4 was low. E2 was inversely associated with body dissatisfaction when P4 was low, but positively associated with body dissatisfaction when P4 was high. However, the simple slopes for the effect of E2 at both high and low P4 were not significant for body dissatisfaction. CONCLUSIONS: Despite the pilot nature of this study, results are broadly consistent with the young adult literature indicating that P4 levels shape the impact of E2 on eating disorder symptoms. Larger studies with the inclusion of key moderators to account for individual heterogeneity are needed to confirm and extend these findings.

Early Life Abuse Moderates the Effects of Intranasal Oxytocin on Symptoms of Premenstrual Dysphoric Disorder: Preliminary Evidence From a Placebo-Controlled Trial.

Background: Although intranasal oxytocin (OXT) has been proposed to be a promising treatment for some psychiatric disorders, little research has addressed individual difference factors that may predict response to OXT. One such factor is early life abuse (ELA), which has widespread influences on social-emotional processing and behavior. This single-blind, placebo-controlled crossover trial examined the role of ELA in shaping the effects of intranasal OXT (vs. placebo) on daily behavioral symptoms in women with three or more prospectively-diagnosed cycling symptoms of premenstrual dysphoric disorder (PMDD). Methods: Participants were ten women with PMDD (n = 8) or subthreshold PMDD (n = 2), who had experienced ELA prior to age 13 (n = 5) or no ELA (n = 5). They completed two study visits during the late luteal (premenstrual) phase: once following administration of intranasal OXT and once following intranasal placebo (counterbalanced). Participants then self-administered OXT or placebo at home three times per day for 5 days or until menstrual onset, and prospectively rated daily emotional symptoms of PMDD. Power was adequate to detect medium main and interactive effects. Results: Among women with ELA, intranasal OXT (vs. placebo) increased the premenstrual emotional symptoms of PMDD, whereas among women without ELA, OXT decreased symptoms. Conclusion: This study adds to a growing literature highlighting the importance of considering historical social contexts and traits (such as ELA) as moderators of therapeutic response to OXT.

Perimenstrual exacerbation of symptoms in borderline personality disorder: evidence from multilevel models and the Carolina Premenstrual Assessment Scoring System.

BACKGROUND: Individuals with a borderline personality disorder (BPD) suffer from a constellation of rapidly shifting emotional, interpersonal, and behavioral symptoms. The menstrual cycle may contribute to symptom instability among females with this disorder. METHODS: Fifteen healthy, unmedicated females with BPD and without dysmenorrhea reported daily symptoms across 35 days. Urine luteinizing hormone and salivary progesterone (P4) were used to confirm ovulation and cycle phase. Cyclical worsening of symptoms was evaluated using (1) phase contrasts in multilevel models and (2) the Carolina Premenstrual Assessment Scoring System (C-PASS), a protocol for evaluating clinically significant cycle effects on symptoms. RESULTS: Most symptoms demonstrated midluteal worsening, a perimenstrual peak, and resolution of symptoms in the follicular or ovulatory phase. Post-hoc correlations with person-centered progesterone revealed negative correlations with most symptoms. Depressive symptoms showed an unexpected delayed pattern in which baseline levels of symptoms were observed in the ovulatory and midluteal phases, and exacerbations were observed during both the perimenstrual and follicular phases. The majority of participants met C-PASS criteria for clinically significant (⩾30%) symptom exacerbation. All participants met the emotional instability criterion of BPD, and no participant met DSM-5 criteria for premenstrual dysphoric disorder (PMDD). CONCLUSIONS: Females with BPD may be at elevated risk for perimenstrual worsening of emotional symptoms. Longitudinal studies with fine-grained hormonal measurement as well as hormonal experiments are needed to determine the pathophysiology of perimenstrual exacerbation in BPD.

Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial.

Importance: The menopause transition and early postmenopausal period are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. Although a few studies suggest that hormone therapy can effectively manage existing depression during this time, to our knowledge, there have been no studies testing whether hormone therapy can prevent the onset of perimenopausal and early postmenopausal depressive symptoms. Objective: To examine the efficacy of transdermal estradiol plus intermittent micronized progesterone (TE+IMP) in preventing depressive symptom onset among initially euthymic perimenopausal and early postmenopausal women. A secondary aim was to identify baseline characteristics predicting TE+IMP's beneficial mood effects. Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial at the University of North Carolina at Chapel Hill from October 2010 to February 2016. Participants included euthymic perimenopausal and early postmenopausal women from the community, aged 45 to 60 years. Interventions: Transdermal estradiol (0.1 mg/d) or transdermal placebo for 12 months. Oral micronized progesterone (200 mg/d for 12 days) was also given every 3 months to women receiving active TE, and identical placebo pills were given to women receiving placebo. Main Outcome Measures: Scores on the Center for Epidemiological Studies-Depression Scale (CES-D), assessed at baseline and months 1, 2, 4, 6, 8, 10, and 12 after randomization, and the incidence of clinically significant depressive symptoms, defined as a CES-D score of at least 16. Results: Of 172 participants, 130 were white (76%), and 70 were African American (19%), with a mean household income of $50 000 to $79 999. The mean age was 51 years, and 43 developed clinically significant depressive symptoms. Women assigned to placebo were more likely than those assigned to TE+IMP to score at least 16 on the CES-D at least once during the intervention phase (32.3% vs 17.3%; odds ratio [OR], 2.5; 95% CI, 1.1-5.7; P = .03) and had a higher mean CES-D score across the intervention period (P = .03). Baseline reproductive stage moderated the effect of treatment (ß, -1.97; SEM, 0.80; P for the interaction = .03) such that mood benefits of TE+IMP vs placebo were evident among women in the early menopause transition (ß, -4.2; SEM, 1.2; P < .001) but not the late menopause transition (ß, -0.9; SEM, 0.3; P = .23) or among postmenopausal women (ß, -0.3; SEM, 1.1; P = .92). Stressful life events in the 6 months preceding enrollment also moderated the effect of treatment on mean CES-D score such that the mood benefits of TE+IMP increased with a greater number of events (ß, 1.22; SEM, 0.40; P = .003). Baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not moderate treatment effects. Conclusions: Twelve months of TE+IMP were more effective than placebo in preventing the development of clinically significant depressive symptoms among initially euthymic perimenopausal and early postmenopausal women. Trial Registration: clinicaltrials.gov Identifier: NCT01308814.

Emotion-related impulsivity and rumination predict the perimenstrual severity and trajectory of symptoms in women with a menstrually related mood disorder.

OBJECTIVE: Women with menstrually related mood disorders (MRMDs) demonstrate clinically significant distress during the premenstrual week that remits with the onset of menses. Relatively little is known about psychosocial mechanisms of MRMDs. Given the core affective and behavioral symptoms of MRMDs, dysfunctional responses to emotion (e.g., difficulties with awareness and regulation of emotion; rumination and impulsive or maladaptive behavior in response to emotion) may be important factors to explore as cognitive and behavioral mechanisms in MRMDs. The purpose of the present study was to examine the associations of various dysfunctional responses to emotion (as measured using the Difficulties in Emotion Regulation Scale [DERS] and brooding on the Ruminative Responses Scale [RRS]) with premenstrual symptom severity and trajectory. METHOD: A total of 54 women (mean age = 38.11; 65% Caucasian) with prospectively confirmed MRMDs completed the DERS and RRS, and provided 2-4 menstrual cycles of daily symptom reports. RESULTS: Only the emotion-related impulsivity subscale of the DERS was robustly associated with premenstrual symptom severity. Brooding rumination predicted a more rapid premenstrual increase and slower postmenstrual remission of some symptoms. CONCLUSION: Both rumination and emotion-related impulsivity may be important treatment targets in cognitive behavioral interventions aimed at reducing symptom severity and cyclicity in MRMDs.