Lee S. Cohen

Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge?

A growing body of literature describes the effects of estrogen and other gonadal steroids on the central nervous system. The ability of estrogen to modulate serotonergic function, in particular, raises the possibility that sex steroids may play a role in the mechanisms associated with depression and its treatment. This review will focus on those aspects of the estrogen-serotonin interaction that relate to possible increased vulnerability to affective disorders and on hormonal treatments that may be clinically applicable to women. After a discussion of the potential relationship between estrogen and mood disorders across the female life cycle, a model is proposed in which differential sensitivity to mood disorders explains the differential response by some women to periods of normal hormonal changes. Possible serotonin receptor-mediated and intracellular mechanisms by which estrogen may exert its effects on mood are also reviewed. These are compared to putative mechanisms of standard antidepressant effect. Lastly, treatment studies in which estrogen has been used as 1) monotherapy for depression, 2) an augmentation strategy, or 3) a prophylactic intervention against recurrence of depression are reviewed.

Estrogen therapy selectively enhances prefrontal cognitive processes: A randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women

Objective: 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 ETs 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. Design: In a double-blind trial, 52 women were randomly assigned to estradiol 0.05 mg/day (n = 26) or placebo transdermal patches (n = 26) for 12 weeks. Women completed tests of memory, learning, and executive functioning, and hot flush and sleep assessments at baseline and study end. A subset of women (five ET treated, six placebo treated) also underwent blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. Results: Nondepressed perimenopausal and postmenopausal women were studied. The majority had hot flushes and sleep impairment. Compared with placebo, ET selectively reduced errors of perseveration during verbal recall (P = 0.03), a frontal system-mediated function, but did not influence other cognitive processes. Women with baseline hot flushes had greater cognitive benefit with ET (P < 0.05). Cognitive benefit was not associated with sleep problems or its improvement. Measures of fMRI BOLD activation during tests of verbal and spatial working memory showed significant increases in frontal system activity with ET (P < 0.001). Conclusions: Estrogen therapy selectively improves executive functioning as demonstrated by reduced perseverative errors and prefrontal cortex activation during verbal recall tasks. Cognitive improvement with ET is associated with hot flushes, but not with sleep, suggesting that ET has a direct central nervous system effect, rather than an indirect effect mediated through improvement of sleep.

Vasomotor symptoms are associated with depression in perimenopausal women seeking primary care.

ObjectiveTo compare the relationship between vasomotor symptoms (hot flushes and night sweats) and depression in perimenopausal women with that in postmenopausal and older premenopausal women. DesignQuestionnaire data assessing current depressive symptoms (Center for Epidemiologic Studies Depression Scale), hot flushes, night sweats, menopausal status, depression history, hormonal therapy use, and demographic characteristics were collected from women aged 40 to 60 years seeking primary care. Multivariable logistic regression models were used to examine the relationship between vasomotor symptoms and depression. ResultsDepression (defined by a Center for Epidemiologic Studies Depression Scale score ≥ 25) was observed in 14.9% of 141 perimenopausal women, 13.9% of 151 postmenopausal women, and 7.6% of 184 older premenopausal women. Recent vasomotor symptoms were reported by 53.9% of perimenopausal women, 43.7% of postmenopausal women, and 20.7% of older premenopausal women. Perimenopausal women with vasomotor symptoms were 4.39 times more likely to be depressed than those without vasomotor symptoms (95% CI, 1.40-13.83), an association that did not change after controlling for depression history. In contrast with perimenopausal women, postmenopausal and older premenopausal women with vasomotor symptoms did not have a significantly greater risk for depression than women of the same menopausal status without vasomotor symptoms (adjusted odds ratios, 1.28 and 1.77; 95% CI, 0.47–3.46 and 0.53–5.89, respectively). ConclusionsHot flushes and night sweats are associated with depression in perimenopausal women. Further investigation is warranted to elucidate the mechanism by which hot flushes may be associated with depression in perimenopausal women and not in postmenopausal or older premenopausal women.

Antidepressant Use in Pregnancy and the Risk of Cardiac Defects

BACKGROUND Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects. METHODS We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders. RESULTS A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41). CONCLUSIONS The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.).

Birth outcomes following prenatal exposure to fluoxetine

BACKGROUND Although pregnancy has frequently been described as a time of emotional well-being, some women experience significant antenatal depression that may require treatment with antidepressants. The purpose of this investigation was to examine the relative effects of early and late trimester exposure to fluoxetine and perinatal outcome. METHODS Obstetric and neonatal records were reviewed for 64 mother-infant pairs where there was documented use of fluoxetine at some point during pregnancy. Differences in several measures of obstetrical outcome and neonatal well-being were examined in early trimester- and late trimester-exposed infants. RESULTS No differences in birth weight and acute neonatal outcome were evident across the two groups, though there was a higher frequency of special care nursery admissions for infants with exposure to fluoxetine late in pregnancy. Special care nursery admissions could not be attributed to any specific factor. CONCLUSIONS Given the growing numbers of women who are treated with antidepressants, including fluoxetine, during pregnancy, and the strong association between depression during pregnancy and risk for postpartum depression, patients may be best advised to continue treatment with antidepressants through labor and delivery versus making any change in intensity of treatment during the acute peripartum period.

Efficacy of Escitalopram for Hot Flashes in Healthy Menopausal Women: A Randomized Controlled Trial

CONTEXT Concerns regarding the risks associated with estrogen and progesterone to manage menopausal symptoms have resulted in its declining use and increased interest in nonhormonal treatments with demonstrated efficacy for hot flashes. OBJECTIVE To determine the efficacy and tolerability of 10 to 20 mg/d escitalopram, a selective serotonin reuptake inhibitor, in alleviating the frequency, severity, and bother of menopausal hot flashes. DESIGN, SETTING, AND PATIENTS A multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel group trial that enrolled 205 women (95 African American; 102 white; 8 other) between July 2009 and June 2010. INTERVENTION Women received 10 to 20 mg/d of escitalopram or a matching placebo for 8 weeks. MAIN OUTCOME MEASURES Primary outcomes were the frequency and severity of hot flashes assessed by prospective daily diaries at weeks 4 and 8. Secondary outcomes were hot flash bother, recorded on daily diaries, and clinical improvement (defined as hot flash frequency ≥50% decrease from baseline). RESULTS Mean (SD) daily hot flash frequency was 9.78 (5.60) at baseline. In a modified intent-to-treat analysis that included all randomized participants who provided hot flash diary data, the mean difference in hot flash frequency reduction was 1.41 (95% CI, 0.13-2.69) fewer hot flashes per day at week 8 among women taking escitalopram (P < .001), with mean reductions of 4.60 (95% CI, 3.74-5.47) and 3.20 (95% CI, 2.24-4.15) hot flashes per day in the escitalopram and placebo groups, respectively. Fifty-five percent of women in the escitalopram group vs 36% in the placebo group reported a decrease of at least 50% in hot flash frequency (P = .009) at the 8-week follow-up. Reductions in hot flash severity scores were significantly greater in the escitalopram group (-0.52; 95% CI, -0.64 to -0.40 vs -0.30; 95% CI, -0.42 to -0.17 for placebo; P < .001). Race did not significantly modify the treatment effect (P = .62). Overall discontinuation due to adverse events was 4% (7 in the active group, 2 in the placebo group). Three weeks after treatment ended, women in the escitalopram group reported a mean 1.59 (95% CI, 0.55-2.63; P = .02) more hot flashes per day than women in the placebo group. CONCLUSION Among healthy women, the use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00894543.

Prevalence and predictors of premenstrual dysphoric disorder (PMDD) in older premenopausal women: The Harvard Study of Moods and Cycles

BACKGROUND Consistent data on the prevalence and predictors of premenstrual dysphoric disorder (PMDD) in the general population are lacking. METHODS Premenstrual symptoms of 4164 women (aged 36-44 years) were retrospectively assessed by the Moos Premenstrual Inventory. From this original sample, 976 subjects were further interviewed at which time demographic and lifestyle characteristics, gynecologic history, and medical conditions were examined. The Structured Clinical Interview for DSM-IV Axis I disorders (SCID) was used to assess past and current psychiatric morbidity. Additionally, 513 of these women completed a prospective evaluation of premenstrual symptoms by using the Daily Rating of Severity of Problems Form (DRSP). RESULTS The diagnosis of PMDD was confirmed in 33 of 513 women (6.4%) who completed the prospective evaluation with daily records. Fourteen subjects (2.7%) met criteria for PMDD without a previous history of depression. PMDD was associated with lower education (odds ratio [OR]=2.3, confidence interval [CI]=1.1-4.9), a history of major depression (OR=3.6, CI=1.7-7.4), and current cigarette smoking (OR=4.1, CI=1.5-11.1). In addition, women not working outside the home were significantly less likely to meet criteria for PMDD (OR=0.2, CI=0.1-0.9). LIMITATIONS Only 513 of 976 women agreed to have their symptoms documented prospectively. Symptoms were assessed over the course of one menstrual cycle. CONCLUSIONS This study indicates a significant prevalence of PMDD in a large community-based sample. Given the associated impairment in social and occupational functioning seen in PMDD, these prevalence data provide a strong rationale for enhanced recognition and treatment of the disorder.

Impact of oral contraceptive pill use on premenstrual mood: Predictors of improvement and deterioration

OBJECTIVES The purpose of this study was to estimate risk factors for the deterioration and improvement of premenstrual mood disturbance with oral contraceptive pill use. STUDY DESIGN Predictors of the deleterious and beneficial effects of oral contraceptive pill use on premenstrual mood were analyzed with the use of logistic regression in a nested case-control study within a community-based cohort of 976 premenopausal women in Massachusetts. RESULTS Of 658 women who were using oral contraceptive pills, 16.3% of the women reported oral contraceptive pill-related premenstrual mood deterioration, and 12.3% of the women reported premenstrual mood improvement. In adjusted models, previous depression was the only significant predictor of mood deterioration (odds ratio, 2.0; 95% CI, 1.1-3.8); early-onset premenstrual mood disturbance and dysmenorrhea were significant predictors of oral contraceptive pill-related mood improvement (odds ratio, 3.1 [95% CI, 1.9-5.2] and odds ratio, 2.3 [95% CI, 1.4-3.9], respectively). CONCLUSION Oral contraceptive pills do not influence premenstrual mood in most women. Premenstrual mood is most likely to deteriorate in women with a history of depression and to improve in women with early-onset premenstrual mood disturbance or dysmenorrhea.

Premenstrual daily fluoxetine for premenstrual dysphoric disorder: a placebo-controlled, clinical trial using computerized diaries.

OBJECTIVE To evaluate premenstrual daily dosing with fluoxetine for treatment of premenstrual dysphoric disorder. METHODS After a two‐cycle screening and one‐cycle single‐blind placebo period, 260 women were randomized to fluoxetine 10 mg, fluoxetine 20 mg, or placebo (dosed daily from 14 days before next expected menses through the first full day of bleeding) for three cycles. Women recorded premenstrual dysphoric disorder symptoms daily using a computerized version of the Daily Record of Severity of Problems. RESULTS Premenstrual daily fluoxetine 20 mg demonstrated significant improvement in mean Daily Record of Severity of Problems luteal scores compared with placebo (P = .005); premenstrual daily fluoxetine 10 mg did not (P = .100). Daily Record of Severity of Problems total scores were statistically significantly improved by the first treatment cycle for both active treatment groups. However, only fluoxetine 20 mg remained statistically significantly superior to placebo throughout the active treatment phase of the trial. Both fluoxetine groups showed significant treatment advantage over placebo for mood‐related symptoms (P < .05). Only premenstrual daily fluoxetine 20 mg showed significant treatment advantage over placebo for physical symptoms of breast tenderness (P < .001), bloating (P = .001), and joint/muscle pain (P = .037). Treatment was well tolerated; discontinuations due to adverse events did not differ among the three groups (P = .316). CONCLUSION Premenstrual daily dosing with fluoxetine effectively treats mood, physical, and social functioning symptoms associated with premenstrual dysphoric disorder. Fluoxetine 20 mg appears to have comparable tolerability with, and better efficacy than, fluoxetine 10 mg.

Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life

Objective: 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. Design: Forty women (aged 40-60 years) with depressive disorders and menopause-related symptoms were randomly assigned to an 8-week open trial with ESCIT (flexible dose, 10-20 mg/day; fixed dose, 10 mg/day for the first 4 weeks) or estrogen plus progestogen therapy (ethinyl estradiol 5 &mgr;g/day plus norethindrone acetate 1 mg/day). Primary outcome measures included Montgomery-Asberg Depression Rating Scale and the Greene Climacteric Scale at week 8. Secondary outcome measures included the Clinical Global Impressions as well as sleep and quality of life assessments. Results: Thirty-two women (16 on EPT, 16 on ESCIT) were included in the analyses. Full remission of depression (score of <10 on the Montgomery-Asberg Depression Rating Scale) was observed in 75% (12/16) of subjects treated with ESCIT, compared to 25% (4/16) treated with EPT (P = 0.01, Fishers exact tests). Remission of menopause-related symptoms (>50% decrease in Greene Climacteric Scale scores) was noted in 56% (9/16) of women treated with ESCIT compared to 31.2% (5/16) on EPT (P = 0.03, Pearsons &khgr;2 tests). Improvement in sleep, hot flashes, and quality of life was observed with both treatments. Conclusions: ESCIT is more efficacious than EPT for the treatment of depression and has a positive impact on other menopause-related symptoms. ESCIT may constitute a treatment option for symptomatic menopausal women who are unable or unwilling to use hormone therapy.