Publications

BACKGROUND: Preliminary reports suggest that menstrual cycle irregularities occur more commonly in women with bipolar disorder and unipolar depression than in the general population. However, it is not always clear whether such abnormalities, reflecting disruption of the hypothalamic-pituitary-gonadal (HPG) axis, are caused by psychotropic treatments or associated with the disorder per se.

METHOD: The prevalence of early-onset (within the first 5 postmenarchal years) menstrual cycle dysfunction (menstrual cycle length unpredictable within 10 days or menstrual cycle length<25 days or >35 days) occurring before onset of psychiatric illness was compared between subjects with DSM-IV bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and subjects with DSM-IV unipolar depression or no psychiatric illness participating in the Harvard Study of Moods and Cycles. Data from the Harvard Study of Moods and Cycles were gathered from September 1995 to September 1997, and data from STEP-BD were gathered from November 1999 to May 2001.

RESULTS: Early-onset menstrual cycle dysfunction was reported to have occurred in 101/295 women with bipolar disorder (34.2%), 60/245 women with depression (24.5%), and 134/619 healthy controls (21.7%). Women with bipolar disorder were more likely to have early-onset menstrual cycle dysfunction than healthy controls (chi2=16.58, p<.0001) and depressed women (chi2=6.08, p=.01), while depressed women were not more likely to have early-onset menstrual cycle dysfunction than healthy controls (chi2=0.81, p=.37).

CONCLUSIONS: Compared with healthy controls and women with unipolar depression, women with bipolar disorder retrospectively report early-onset menstrual dysfunction more commonly prior to onset of bipolar disorder. Future studies should evaluate potential abnormalities in the hypothalamic-pituitary-gonadal axis that are associated with bipolar disorder.

BACKGROUND: Preliminary evidence suggests that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of PCOS features after initiation of valproate was therefore examined in women with bipolar disorder using a standardized definition of PCOS.

METHODS: Three hundred women 18 to 45 years old with bipolar disorder were evaluated for PCOS at 16 Systematic Treatment Enhancement for Bipolar Disorder sites. A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, elevated androgens) with oligoamenorrhea that developed while taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained, and hyperandrogenism was assessed.

RESULTS: Among 230 women who could be evaluated, oligoamenorrhea with hyperandrogenism developed in 9 (10.5%) of 86 women on valproate and in 2 (1.4%) of 144 women on a nonvalproate anticonvulsant or lithium (relative risk 7.5, 95% confidence interval [CI] 1.7-34.1, p = .002). Oligoamenorrhea always began within 12 months of valproate use.

CONCLUSIONS: Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism. Monitoring for reproductive-endocrine abnormalities is important when starting and using valproate in reproductive-aged women. Prospective studies are needed to elucidate risk factors for development of PCOS on valproate.

BACKGROUND: In the Systematic Treatment Enhancement Program for Bipolar Disorder, we showed that valproate is associated with new-onset menstrual-cycle irregularities and hyperandrogenism in 10.5% of 86 women. We now determine whether polycystic ovarian syndrome (PCOS) features reverse on valproate discontinutation.

METHODS: Women with valproate-associated PCOS and those at risk for PCOS (valproate use < or =6 months) were re-evaluated for PCOS.

RESULTS: Follow-up (mean 17 months) assessments were completed in 14 women (5 with treatment-emergent PCOS, 9 on valproate < or =6-month). Of seven women who developed valproate-associated PCOS, PCOS reproductive features remitted in three of four discontinuing valproate and persisted in all 3 continuing valproate. Menstrual-cycle irregularities improved among valproate-discontinuers whose PCOS features remitted (p = 0.01). There was a trend toward lower serum testosterone (p = 0.06). Body-weight and polycystic ovarian morphology did not change.

CONCLUSIONS: In the first longitudinal bipolar-disorder study of valproate-associated PCOS, most valproate-discontinuers had improved reproductive features of PCOS despite static body-weight.

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 microg/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, Fisher's 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, Pearson's chi2 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.

OBJECTIVE: To examine whether physical activity was associated with decreased risk of vasomotor symptoms in a prospective study of women transitioning through menopause.

DESIGN: Hypotheses were evaluated in the Harvard Study of Moods and Cycles, a longitudinal study of women with and without a history of major depression (N = 523). Ordinal logistic regression models were utilized to assess the odds of vasomotor symptoms (none, mild, moderate/severe; Greene Climacteric Scale) associated with physical activity (quartiles of metabolic equivalent-hours per week) at study enrollment and over a 3- to 5-year follow-up period.

RESULTS: No significant associations between physical activity and vasomotor symptoms were observed for the sample as a whole. However, exploratory analyses stratified by depression history revealed that among the 157 women with a lifetime history of major depression, high (odds ratio [OR] = 0.28, 95% CI: 0.09-0.83) or moderately high (OR = 0.33, 95% CI: 0.11-0.99) physical activity proximal to the vasomotor assessment, as well as consistently high (OR = 0.27, 95% CI: 0.10-0.75) or increasing (OR = 0.33, 95% CI: 0.12-0.92) physical activity over the duration of the 3- to 5-year follow-up period was associated with decreased vasomotor symptoms relative to sedentary behavior. No significant associations were observed for women without a history of depression.

CONCLUSIONS: Physical activity may be associated with decreased risk of vasomotor symptoms among women with a history of major depression.

OBJECTIVE: To evaluate eszopiclone 3 mg for treatment of insomnia in perimenopausal and early postmenopausal women, as well as the impact of insomnia treatment on mood, menopause-related symptoms, and quality of life.

METHODS: This was a double-blind, placebo-controlled study with 410 women (aged 40-60; perimenopausal or early postmenopausal) who reported insomnia defined as sleep latency of at least 45 minutes and total sleep time less than or equal to 6 hours per night for at least 3 nights per week over the previous month. Patients were randomly assigned to eszopiclone 3 mg or placebo nightly for 4 weeks. Sleep data were collected once a day. Physician global assessments of menopause, menopause-specific questionnaire, Greene Climacteric Scale, the Montgomery Asberg Depression Rating Scale, and the Sheehan Disability Scale were collected at baseline and end of treatment.

RESULTS: Patients receiving eszopiclone reported improvements in sleep induction, sleep maintenance, sleep duration, sleep quality, and next-day functioning relative to placebo (P<.05). Patients receiving eszopiclone reported fewer total awakenings and awakenings due to hot flushes (P<.05). Eszopiclone use led to greater improvement in Montgomery Asberg Depression Rating Scale scores (P<.05) and physician global assessments of menopause scores (P<.001); total Greene Climacteric Scale score and the vasomotor and psychological sub-scores (P<.05); vasomotor and physical domains of the menopause-specific questionnaire (P<.05); and family life/home domain of the Sheehan Disability Scale (P<.05).

CONCLUSION: In this study, eszopiclone provided significant improvements in sleep and positively impacted mood, quality of life, and menopause-related symptoms in perimenopausal and early postmenopausal women with insomnia.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00366093

LEVEL OF EVIDENCE: I.

Recent census data indicate that, in the United States, an increasing number of women–almost 1.5 million each year–are reaching menopause. The menopausal transition is marked by intense hormonal fluctuations, and may be accompanied by vasomotor complaints, sleep disturbances, changes in sexual function, and increased risk for osteoporosis and cardiovascular disease. In addition, there is evidence of increased risk for developing depression, even among women who never experienced depressive symptoms before. Thus depression during the perimenopause may have a substantial impact on personal, family, and professional spheres of life. A challenge to clinicians and health professionals lies in the identification of the most tolerable treatments to manage depression and improve quality of life in an aging population. Any treatment strategy should take into account not only the spectrum of side effects that may complicate treatment but also other menopause-related factors (e.g., vasomotor symptoms, psychosocial stressors) that may modulate risk for the development of mood disturbance. This article reviews the current literature on the prevalence and risk factors associated with depression during the menopausal transition. The benefits and risks of using hormonal and nonhormonal strategies for the management of depression and other menopause-related somatic symptoms are critically reviewed.

OBJECTIVE: To examine gender differences in a large sample of patients with bipolar illness.

METHODS: Exploratory analysis of baseline data from the first 500 patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a multi-center NIMH project. Participants are allowed to have medical and psychiatric comorbidities, and to enter in any mood state, thus making the population more generalizable than many research cohorts. Diagnoses and history were assessed using structured clinical instruments administered by certified investigators. Given the exploratory nature of these analyses, there is no correction of for multiple comparisons. However, we emphasize findings that are statistically significant at the more stringent p < 0.01 level.

RESULTS: Compared with men, women had higher rates of BPII (15.3% M versus 29.0% F, p < 0.01), comorbid thyroid disease (5.7% M versus 26.9% F, p < 0.01), bulimia (1.5% M versus 11.6% F, p < .0.01) and post-traumatic stress disorder (10.6% M versus 20.9% F, p < 0.01). Women and men had equal rates of history of lifetime rapid cycling and depressive episodes. Men were more likely to have a history of legal problems (36% M versus 17.5% F, p < 0.01).

CONCLUSIONS: Potentially important gender differences in certain illness characteristics were found in our study; however, in contrast to other reports, we did not find higher rates of lifetime depressive episodes or rapid cycling in women. Although our study is limited by its retrospective study design, its results are strengthened by our large sample size and use of structured interviews.

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.

More than 1 million women are expected to reach menopause each year, many of whom will experience hot flushes and other neuropsychological symptoms that may diminish their quality of life. Hot flushes are the core symptoms that reflect the brain's response to the changing hormonal milieu of the menopause transition, particularly to the rapidly fluctuating and falling levels of estradiol. The physical symptoms of hot flushes and the associated changes in sleep, mood, and cognition will lead many women to seek medical care. It is critical to understand the interrelationship of hot flushes and other neuropsychological symptoms of the menopause transition so that treatment priorities can be established. For example, if sleep disruption explains most daytime neuropsychological problems in women with hot flushes, treating insomnia should be considered a priority. Alternatively, mood, cognition, and quality of life may be disturbed independent of sleep problems. In such a situation, each symptom should be evaluated separately from any assessment of sleep. As recent data from the WHI establish the risks of long-term HRT use, concern about using HRT, even as a short-term intervention, has increased substantially. Although HRT remains the first-line treatment for hot flushes, the WHI findings have drawn attention to nonhormonal treatments of hot flushes and other menopausal symptoms. Growing evidence to support the efficacy of serotonergic antidepressants and other psychoactive medications in the treatment for hot flushes suggests that nonhormonal interventions will prove important alternatives to HRT. As further evidence of the benefits of psychoactive medications for menopausal symptoms is established, the choice between using hormonal and nonhormonal therapies for management of menopausal symptoms will continue to evolve.