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AbstractDue to their genomic variants, some individuals are more highly affected by toxicants than others. Toxicant metabolizing and activating variants have been linked with a wide variety of health issues including an increased risk of miscarriages, birth defects, Alzheimer’s, benzene toxicity, mercury toxicity and cancer. The study of genomics allows a clinician to identify pathways that are less effective and then gives the clinician the opportunity to counsel their patients about diet, supplements and lifestyle modifications that can improve the function of these pathways or compensate to some extent for their deficits. This article will review a few of these critical pathways relating to phase I and phase 2 detox such as GSTP1, GPX1, GSTT1 deletions, PON1 and some of the CYP 450 system as examples of how an individual's genomic vulnerabilities to toxicants can be addressed by upregulating or downregulating specific pathways via genomically targeted use of foods, supplements and lifestyle changes.

Risks, benefits, alternatives, and appropriateness of psychotropic medications, including risks of no treatment, are discussed for antidepressants, mood-stabilizing medications, anxiolytic/sedative hypnotic medications, stimulants, and medication-assisted treatment of substance use disorders. Early screening, diagnosis, and intervention prior to and/or during pregnancy often reduce morbidity and mortality of mental health disorders for mothers and infants.

Obesity during pregnancy is the most common high-risk obstetric condition, resulting in increased rates of adverse maternal and neonatal outcomes. Individuals with psychiatric disorders have a higher risk of obesity than the general population, but data regarding implications of obesity in women with psychiatric disorders are sparse.

Context:Women are at increased risk for mood disturbance during the menopause transition. Hot flashes (HFs), sleep disruption, and fluctuating estradiol levels correlate with menopause-associated depression but co-occur, making cause and effect relationships difficult to disentangle.Objective:Using a GnRH agonist (GnRHa) experimental model, we investigated whether depressive symptoms are associated with HFs and/or are explained by concomitant sleep fragmentation in the absence of estradiol fluctuation.Design and Intervention:Depressive symptoms, objective polysomnographic sleep parameters, subjective sleep quality, serum estradiol, and HFs were assessed before and 4 weeks after open-label depot GnRHa (leuprolide 3.75-mg) administration.Setting:Academic medical center.Participants:Twenty-nine healthy nondepressed premenopausal volunteers (mean age, 27.3 years).Results:Serum estradiol was rapidly and uniformly suppressed. HFs developed in 69% of the subjects. On univariate analysis, worsening of mood was predicted by increases in time in light sleep (stage N1), number of transitions to wake, non-REM arousals, subjective sleep quality, and reductions in perceived sleep efficiency (all P< .045), as well as the number of nighttime (P= .006), but not daytime (P= .28), HFs reported. In adjusted models, the number of nighttime HFs reported, increases in non-REM arousals, time in stage N1, transitions to wake, and reduced sleep quality remained significant predictors of mood deterioration (P≤ .05).Conclusions:Depressive symptoms emerged after estradiol withdrawal in association with objectively and subjectively measured sleep disturbance and the number of nighttime, but not daytime, HFs reported. Results suggest that sleep disruption and perceived nighttime HFs both contribute to vulnerability to menopause-associated depressive symptoms in hypoestrogenic women.

IMPORTANCE: Effective, practical, nonpharmacologic therapies are needed to treat menopause-related insomnia symptoms in primary and women’s specialty care settings. OBJECTIVE: To evaluate the efficacy of telephone-based cognitive behavioral therapy for insomnia (CBT-I) vs menopause education control (MEC). DESIGN, SETTING, AND PARTICIPANTS: A single-site, randomized clinical trial was conducted from September 1, 2013, to August 31, 2015, in western Washington State among 106 perimenopausal or postmenopausal women aged 40 to 65 years with moderate insomnia symptoms (Insomnia Severity Index [ISI] score, ≥12) and 2 or more daily hot flashes. Blinded assessments were conducted at baseline, 8, and 24 weeks postrandomization. An intent-to-treat analysis was conducted. INTERVENTIONS: Six CBT-I or MEC telephone sessions in 8 weeks. Participants submitted weekly electronic sleep diaries and received group-specific written educational materials. The CBT-I sessions included sleep restriction, stimulus control, sleep hygiene education, cognitive restructuring, and behavioral homework; MEC sessions provided information about menopause and women’s health. MAIN OUTCOMES AND MEASURES: Primary outcome was scores on the ISI (score range, 0-28; scores ≥15 indicate moderate to severe insomnia). Secondary outcome was scores on the Pittsburgh Sleep Quality Index (score range, 0-21; higher scores indicate worse sleep quality). Additional outcomes included sleep and hot flash diary variables and hot flash interference. RESULTS: At 8 weeks, ISI scores had decreased 9.9 points among 53 women receiving CBT-I (mean [SD] age, 55.0 [3.5] years) and 4.7 points among 53 women receiving MEC (age, 54.7 [4.7] years), a mean between-group difference of 5.2 points (95% CI, –6.1 to –3.3; P &lt; .001). Pittsburgh Sleep Quality Index scores decreased 4.0 points in women receiving CBT-I and 1.4 points in women receiving MEC, a mean between-group difference of 2.7 points (95% CI, –3.9 to –1.5; P &lt; .001). Significant group differences were sustained at 24 weeks. At 8 and 24 weeks, 33 of 47 women (70%) and 37 of 44 (84%) in the CBT-I group, respectively, had ISI scores in the no-insomnia range compared with 10 of 41 (24%) and 16 of 37 (43%) in the MEC group, respectively. The CBT-I group also had greater improvements in diary-reported sleep latency, wake time, and sleep efficiency. There were no between-group differences in frequency of daily hot flashes, but hot flash interference was significantly decreased at 8 weeks for the CBT-I group (–15.7; 95% CI, –20.4 to –11.0) compared with the MEC group (–7.1; 95% CI, –14.6 to 0.4) (P = .03), differences that were maintained at 24 weeks for the CBT-I group (–22.8; 95% CI, –28.6 to –16.9) and MEC group (–11.6; 95% CI, –19.4 to –3.8) (P = .003). CONCLUSIONS AND RELEVANCE: Telephone-based CBT-I improved sleep in perimenopausal and postmenopausal women with insomnia and hot flashes. Results support further development and testing of centralized CBT-I programs for treating menopausal insomnia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01936441

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This study aims to evaluate the effects of low-dose estradiol (E2) or venlafaxine on menopause-related quality of life and associated symptoms in healthy perimenopausal and postmenopausal women with hot flashes.

Premature birth is associated with infant morbidity and mortality. Women with psychiatric disorders represent an at-risk population for premature delivery and other obstetrical complications. The primary aim of this study was to assess the association between omega-3 fatty acid use and length of gestation.

Many women discontinue antidepressants (ADs) when trying to conceive, although risk of depressive relapse is high. We examined the feasibility and potential clinical effect of cognitive behavioral therapy for the prevention of recurrence (CBT-PR) for women with a history of recurrent major depressive disorder (MDD) who planned to discontinue maintenance AD treatment for pregnancy.

IMPORTANCE: Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date. OBJECTIVE: To determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS). DESIGN, SETTING, AND PARTICIPANTS: In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012. INTERVENTIONS: Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments. RESULTS: Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P &lt; .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P &lt; .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated. CONCLUSIONS AND RELEVANCE: Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01418209

This study aims to determine the efficacy and tolerability of omega-3 fatty acids in reducing vasomotor symptoms (VMS) frequency and bother in perimenopausal and postmenopausal women.

This study aims to determine the efficacy of yoga in alleviating vasomotor symptoms (VMS) frequency and bother.

This study aims to determine the efficacy of exercise training for alleviating vasomotor and other menopausal symptoms.

This report describes the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network and methodological issues addressed in designing and implementing vasomotor symptom trials.

Vasomotor symptoms (VMS) recur after discontinuation of hormonal therapy. Selective serotonin reuptake inhibitors (SSRIs) are used increasingly to treat VMS, but whether VMS recur after cessation of SSRI is unknown. We hypothesized that relapse of VMS to baseline levels after SSRI cessation would be common and predicted by menopausal and psychological characteristics.

We sought to obtain preliminary data regarding the efficacy of omega-3 fatty acids for major depressive disorder associated with the menopausal transition. Secondary outcomes were assessed for vasomotor symptoms (or hot flashes).

This study assessed the efficacy, safety, and tolerability of the serotonin-norepinephrine reuptake inhibitor desvenlafaxine and the selective serotonin reuptake inhibitor escitalopram for major depressive disorder (MDD) in postmenopausal women.

Depression occurs more commonly during the menopausal transition in women with vasomotor symptoms (VMS) than in those without, but most women with VMS do not develop depression. It has been hypothesized that VMS are associated with depression because VMS lead to repeated awakenings, which impair daytime well-being. We aimed to determine if objectively measured sleep and perceived sleep quality are worse in depressed women with VMS than in nondepressed women with VMS.

ARNO is a soluble guanine nucleotide exchange factor (GEF) for the Arf family of GTPases. Although in biochemical assays ARNO prefers Arf1 over Arf6 as a substrate, its localization in cells at the plasma membrane (PM) suggests an interaction with Arf6. In this study, we found that ARNO activated Arf1 in HeLa and COS-7 cells resulting in the recruitment of Arf1 on to dynamic PM ruffles. By contrast, Arf6 was activated less by ARNO than EFA6, a canonical Arf6 GEF. Remarkably, Arf6 in its GTP-bound form recruited ARNO to the PM and the two proteins could be immunoprecipitated. ARNO binding to Arf6 was not mediated through the catalytic Sec7 domain, but via the pleckstrin homology (PH) domain. Active Arf6 also bound the PH domain of Grp1, another ARNO family member. This interaction was direct and required both inositol phospholipids and GTP. We propose a model of sequential Arf activation at the PM whereby Arf6-GTP recruits ARNO family GEFs for further activation of other Arf isoforms.

ARNO is a soluble guanine nucleotide exchange factor (GEF) for the Arf family of GTPases. Although in biochemical assays ARNO prefers Arf1 over Arf6 as a substrate, its localization in cells at the plasma membrane (PM) suggests an interaction with Arf6. In this study, we found that ARNO activated Arf1 in HeLa and COS-7 cells resulting in the recruitment of Arf1 on to dynamic PM ruffles. By contrast, Arf6 was activated less by ARNO than EFA6, a canonical Arf6 GEF. Remarkably, Arf6 in its GTP-bound form recruited ARNO to the PM and the two proteins could be immunoprecipitated. ARNO binding to Arf6 was not mediated through the catalytic Sec7 domain, but via the pleckstrin homology (PH) domain. Active Arf6 also bound the PH domain of Grp1, another ARNO family member. This interaction was direct and required both inositol phospholipids and GTP. We propose a model of sequential Arf activation at the PM whereby Arf6-GTP recruits ARNO family GEFs for further activation of other Arf isoforms.

To examine the efficacy and tolerability of escitalopram (ESCIT) compared to estrogen and progestogen therapy (EPT) for the treatment of symptomatic peri- and postmenopausal women.

Estrogen therapy (ET) seems to differentially effect cognitive processes in younger versus older postmenopausal women, suggesting a window of opportunity when ET is most beneficial. Cognitive improvement in younger postmenopausal women has been attributed to ET's influence on hot flushes and sleep, but empiric examination of the mediating role of menopause symptoms versus direct effects of ET on the brain is limited.

Focal adhesion kinase (FAK) is a tyrosine kinase whose phosphorylation state and activity is tightly linked to cell adhesion to the extracellular matrix through integrin receptors. FAK's regulation by adhesion places it in a key position to be able to influence cellular events that are either dependent on cell adhesion like cell proliferation and survival, or that require modulation of cell adhesion like cell migration. FAK's involvement in cellular pathways that regulate cell growth and cell movement suggests that it may contribute to the development of cancer or other diseases. FAK's possible involvement in these pathways makes it a potential drug target. In this review we will focus on the developing view how FAK's activity and phosphorylation are regulated within the cell. Specifically, we will address the contribution of integrins and growth factor dependent pathways to FAK's activation. The role of the tyrosine kinase Src in FAK's regulation will be discussed. The contribution of various negative regulators of FAK's phosphorylation on its regulation including phosphatases and proteases will be discussed. Lastly, the emerging role of FAK's amino terminal FERM like domain in FAK's regulation will be explored. FAK's function within a cell are tightly linked to its phosphorylation state, thus understanding its normal regulation in the cell will provide important insight into drug development by highlighting novel regulatory mechanisms within FAK that potentially may be exploited.

The objective of this study was to examine the efficacy and tolerability of intermittent dosing of venlafaxine for the treatment of premenstrual dysphoric disorder. One hundred and twenty-four women aged 18 to 45 years, with regular menstrual cycles and who reported significant premenstrual symptoms, were assessed prospectively to confirm their diagnosis of premenstrual dysphoric disorder. Twenty subjects with confirmed premenstrual dysphoric disorder entered a single-blind, placebo phase (1 cycle). Placebo nonresponders (n = 12) received 2 cycles of intermittent (premenstrual) treatment with venlafaxine (75 to 112.5 mg/d). Subjects initiated treatment 14 days before the anticipated onset of menses and discontinued it on the second day of bleeding. Doses could be adjusted after cycle 1 based on subjects' response and tolerability. Response to treatment was assessed based on changes in the Daily Rating Severity of Problems and Premenstrual Tension Syndrome Questionnaire scores from baseline (before the placebo cycle), as well as Clinical Global Impression-Severity scores. Discontinuation symptoms were assessed between treatment cycles, using the Discontinuation-Emergent Signs and Symptoms questionnaire. Eleven subjects concluded 2 cycles of intermittent dosing with venlafaxine. Nine subjects (81.8%) showed satisfactory response based on Clinical Global Impression of ≤2. Changes in Daily Rating Severity of Problems scores and subscores (depression, physical symptoms, and anger) and in Premenstrual Tension Syndrome Questionnaire scores were significant (P< 0.05 for all comparisons, Wilcoxon tests). Intermittent treatment was well tolerated. This preliminary report suggests that premenstrual use of venlafaxine is an efficacious and well-tolerated treatment for premenstrual dysphoric disorder.

ABSTRACTPregnancy has frequently been described as a time of affective well-being. However, a growing literature suggests that women are neither “protected” against new-onset or recurrence of depression during this time. Diagnosis and effective treatment of depression during pregnancy requires a careful weighing of risk of treatment which may include psychotropic medications against the risks associated with failure to adequately manage affective distress and its potential impact of maternal and fetal well-being. Treatment options during pregnancy are reviewed in the context of developing the most appropriate risk/benefit decision for individual patients with past or current depression who either anticipate pregnancy or who become pregnant.