Claudio N. Soares

Background: Preliminary clinical evidence indicates that menopausal status might impact on the efficacy of certain classes of antidepressants. Objective: The aim of this study was to evaluate open-label desvenlafaxine treatment (administered as desvenlafaxine succinate) in postmenopausal women who did not achieve clinical response to acute, double-blind treatment with desvenlafaxine or escitalopram. Study Design: This phase IIIb, multicentre study included a 6-month open-label extension phase of patients who did not respond in the initial 8-week, randomized, double-blind acute phase. Patients: Postmenopausal women aged 40–70 years with a primary diagnosis of major depressive disorder were recruited. Primary Intervention: Non-responders to acute treatment with double-blind desvenlafaxine or escitalopram received flexible-dose, open-label desvenlafaxine 100–200 mg/day for the 6-month extension phase. Main Outcome Measure: The primary efficacy assessment was the 17-item Hamilton Rating Scale for Depression (HAM-D₁₇) total score. Secondary efficacy outcome measures were the Clinical Global Impressions-Improvement (CGI-I) and -Severity scales, Hamilton Rating Scale for Anxiety, Quick Inventory of Depressive Symptomatology-Self-Report, Visual Analogue Scale-Pain Intensity and the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary health assessments were the Changes in Sexual Functioning Questionnaire, 5-Dimension EuroQoL Index, Health State Today, Menopause Rating Scale, Sheehan Disability Scale, treatment response (≥50% decrease in total HAM-D₁₇ and MADRS score from acute-phase baseline and CGI-I total score ≤2), HAM-D₁₇ remission (total score ≤7) and safety. Descriptive statistics were used to summarize outcomes. Results: The efficacy analysis included 123 patients (desvenlafaxine/ desvenlafaxine = 64; escitalopram/desvenlafaxine = 59). At final evaluation of the open-label extension phase, mean reductions from acute-phase baseline in HAM-D₁₇ total scores were −11.33 for the desvenlafaxine/desvenlafaxine group and −11.41 for the escitalopram/desvenlafaxine group. HAM-D₁₇ response or remission after 6 months of open-label extension phase desvenlafaxine treatment were achieved in 56–58% and 41–48% of patients, respectively. The results of the other secondary efficacy outcome measures and other definitions of treatment response were generally consistent with the primary analyses. The observed adverse events were similar to those reported during previous desvenlafaxine clinical trials. Conclusions: Postmenopausal women with major depressive disorder who did not respond to acute, double-blind treatment with escitalopram or desvenlafaxine achieved modest, continued improvement with long-term, open-label desvenlafaxine therapy. Further interpretation of these findings is limited by aspects of the study design (i.e. open-label, non-placebo-controlled) and the lack of randomized comparison groups in the extension phase, which prevents statistical assessment of the efficacy of longer term treatment with desvenlafaxine. Clinicaltrials.gov identifier: NCT00406640.

Hot flashes (or flushes) are the most commonly reported symptoms during the menopause transition and early postmenopausal years, particularly in Western societies; they affect 60–90% of women and can lead to significant physical discomfort and functional impairment. The emergence of hot flashes and night sweats (also known as vasomotor symptoms [VMS]) coincide with a period in life that is also marked by dynamic changes in hormone and reproductive function that interconnect with the aging process, changes in metabolism, lifestyle behaviours and overall health. Estrogen-based therapies have long been the treatment of choice for women suffering from VMS. More recent concerns over long-term safety of menopausal hormone treatments, however, have led physicians and patients to pursue non-hormonal strategies to alleviate their symptoms. In this article, we review most of the efficacy and safety data on non-hormonal treatments for VMS published over the past 20 years. We discuss the evidence for treating symptomatic women in different clinical scenarios, e.g. VMS with and without concomitant depression or VMS following the use of anti-estrogen therapies. Overall, efficacy data support the use of some psychotropic medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and gabapentin. Complementary and alternative methods for VMS also showed limited but promising results, although more definitive studies are warranted. Clinicians should therefore be abl to tailor treatment strategies for those who are unable or unwilling to use hormones to alleviate VMS and improve overall functioning and quality of life.

There is little doubt that women experience a heightened psychiatric morbidity compared to men. A growing body of evidence suggests that, for some women, the menopausal transition and early postmenopausal years may represent a period of vulnerability associated with an increased risk of experiencing symptoms of depression, or for the development of an episode of major depressive disorder. Recent research has begun to shed some light on potential mechanisms that influence this vulnerability. At the same time, a number of studies and clinical trials conducted over the past decade have provided important data regarding efficacy and safety of preventative measures and treatment strategies for midlife women; some of these studies have caused a shift in the current thinking of how menopausal symptoms should be appropriately managed.

Perimenopausal and early postmenopausal women have shown an increased risk for developing depression (new onset or recurrent); concomitant vasomotor and other menopause-related complaints significantly affect quality of life and overall functioning. This study examined the effects of quetiapine extended release (XR) in midlife women with major depressive disorder who also reported significant menopause-related symptoms. Forty eligible women with major depressive disorder entered a 2-week, placebo lead-in phase, followed by an 8-week open trial with quetiapine XR, flexible dose, 150-300 mg/d. The primary outcome measure (depressive symptoms) was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Other measures included menopause symptoms (Greene Climacteric Scale total scores and subscores) and the impact of hot flashes on functioning (Hot Flash-Related Daily Interference Scale). Weight, cholesterol, triglycerides, and glucose levels were monitored. Data from 24 subjects (modified intent-to-treat, last observation carried forward; quetiapine XR mean dose, 191 [SD, 55] mg/d) showed improvement in depressive and menopause-related symptoms, that is, reduction in MADRS, GCS, and Hot Flash-Related Daily Interference Scale scores (P < 0.01 for all comparisons). Seventeen subjects were considered responders (>50% reduction in MADRS scores); 15 achieved remission (MADRS<10). Main adverse effects included drowsiness and dry mouth. Based on these preliminary results, quetiapine XR should be further examined in larger, controlled trials for the management of depressed, symptomatic midlife women.

Epidemiological and clinic data support the notion that some women may be at higher risk for developing mood and anxiety symptoms and cognitive complaints during certain periods in life that are marked by intense hormone variations and psychosocial stressors. The complexity of the so-called windows of vulnerability poses a particular challenge to professionals involved in the care of female patients. Menopausal transition is perhaps a paramount example; the process itself is marked by progressive, dynamic changes in hormone levels and reproductive function that interact with the aging process, changes in metabolism, sexuality, lifestyle behaviors, and overall health.The putative compounded burden of health challenges associated with this transition has become a main focus of attention of physicians and researchers who aim to identify preventive and/or early intervention strategies to promote healthy aging in midlife women. Recent studies have provided further evidence that the menopausal transition may be not only a window of vulnerability for depression and cognitive impairment but also a critical "window of opportunity" for the success of hormone-based treatments.The need for further investigation and better understanding of common underlying mechanisms seems intuitive. An ultimate goal could include preventive strategies for women presenting with various risk factors for cardiovascular, cognitive, and mood disorders as well as treatments that could be tailored to multiple symptom domains during the menopausal transition.

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. In this randomized, double-blind study, postmenopausal outpatients (aged 40-70 y) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition MDD received flexible-dose desvenlafaxine (100-200 mg/d) or escitalopram (10-20 mg/d) for 8 weeks. Acute-phase responders, that is, women with a 50% or greater reduction from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, were eligible to continue the same double-blind treatment in the 6-month continuation phase. The primary efficacy outcomes were mean change from baseline in HAM-D17 total score (acute phase), analyzed using a mixed-effects model for repeated measures, and the proportion of women who maintained response (continuation phase), analyzed using logistic regression. Reductions in HAM-D17 total score at acute-phase endpoint were similar for desvenlafaxine- and escitalopram-treated women (-13.6 vs -14.3, respectively; P = 0.24). No significant difference was observed between groups at continuation-phase endpoint in the proportion of women who maintained response (desvenlafaxine, 82%; escitalopram, 80%; P = 0.70). In both phases, desvenlafaxine and escitalopram were generally safe and well tolerated. Among postmenopausal outpatients with MDD, there were no significant differences in the efficacy of desvenlafaxine and escitalopram based on primary efficacy analyses. The results do not support the overall hypothesis that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine has an efficacy advantage for the treatment of MDD in postmenopausal women because, in this particular subgroup, desvenlafaxine failed to prove superiority over escitalopram. Safety and tolerability were comparable.