Hot flashes and antidepressant agents: uneasy bedfellows.

A lthough hot flashes are one of the most common and distressing symptoms associated with menopause, postmenopausal women also experience multiple other bothersome symptoms, including sleep disturbances. Epidemiological studies have shown that difficulties with sleep are more common in perimenopausal and postmenopausal womenVwith a prevalence of around 40%Vthan in premenopausal women. The exact etiology of sleep difficulties in postmenopausal women remains unclear. It is hypothesized that these difficulties may be related to the menopausal transition, changes in hormonal levels, psychological distress or mood disorders, or other primary sleep disorders. A pervasive question concerns the relationship between hot flashes and sleep disturbances in postmenopausal women. Women who experience hot flashes commonly report increased difficulty sleeping and increased nighttime awakenings, yet previous studies have questioned this relationship. Freedman and Roehrs performed a study in which symptomatic and asymptomatic postmenopausal and premenopausal women were monitored during sleep and assessed for the relationship between hot flashes and disordered sleep. In this study, most awakenings precededVrather than followedVhot flashes, suggesting that hot flashes did not produce sleep disturbances. However, in a second study, Freedman and Roehrs reported an association between hot flashes and sleep disturbances, with this association being more prevalent during the first half of the night. In addition, another study, which measured hot flashes with a skin conductance device, failed to show a relationship between device-detected hot flashes and sleep disturbances, despite there being an association between self-reported hot flashes and shortterm sleep problems. Nonetheless, more recently multiple, prospective, survey studies supported a relationship between hot flashes and sleep disturbances in postmenopausal women. Currently, hormone therapy is the most effective treatment for hot flashes, with reductions of 80% to 90% with estrogen therapy. However, because of safety concerns, hormone therapy is often avoided in women and, when used, the lowest dose for the shortest duration is recommended. This has led to substantial research investigating nonYhormone therapies for the treatment of hot flashes. Gabapentin and pregabalin have been shown to produce benefits, with reductions in hot flash scores of about 60%, compared with placebo-associated reductions of about 25%. Multiple selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including paroxetine, venlafaxine, desvenlafaxine, citalopram, fluoxetine, and sertraline, have been investigated for the treatment of hot flashes, with hot flash score reductions of about 60%. Escitalopram, an SSRI, has also recently been studied as a treatment for hot flashes in a multicenter, randomized, placebo-controlled trial involving healthy postmenopausal women. The recently published primary results of this trial report that women treated with escitalopram had a decrease in hot flash frequency and severity compared with placebo. The sole trial that prospectively compared an antidepressant agent (venlafaxine) to gabapentin in a randomized crossover manner reported that women preferred venlafaxine to gabapentin by a 2:1 margin. Despite convincing evidence demonstrating the efficacy of SSRIs and SNRIs for the treatment of hot flashes and the increasing clinical use of these drugs for hot flashes, there remain concerns regarding the potential adverse effects of SSRI and SNRI treatment, including gastrointestinal adverse effects, sexual dysfunction, and somnolence. In addition, a commonly feared adverse effect of SSRIs and SNRIs is insomnia, with this symptom being listed as a frequently reported adverse event associated with the use of these drugs. Previous studies have reported that these antidepressant agents have a negative impact on sleep, including suppression of rapid eye movement sleep and increased nocturnal arousals. However, despite polysomnographic abnormalities being found with SSRI administration in healthy volunteers, subjective assessments often have revealed unchanged, or even improved, sleep. In addition, although many studies have shown objective and subjective sleep disturbances with SSRIs and SNRIs in women with mood disorders, others have failed to show these effects and even demonstrated improvements in sleep problems. As postmenopausal women already have increased sleep difficulties, exploring the effects of SNRIs and SSRIs on sleep in women being treated for hot flashes is important. Ensrud et al, in the current issue of Menopause, report on secondary outcomes from their previously published study of escitalopram for the treatment of hot flashes in healthy postmenopausal women. In their study, insomnia symptoms were measured by the Insomnia Severity Index (ISI), and subjective sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI). These measures were assessed in weeks 4 and 8 in women being treated with escitalopram versus placebo. The authors report that women treated with escitalopram had an improvement in insomnia symptoms and subjective sleep quality, with statistically significant improvements in ISI and PSQI scores in week 8. At baseline, many of the women in this trial had evidence of sleep disturbances, with a mean ISI score of 11.4, consistent with mild insomnia. In addition, 40% of women had a PSQI score higher than 8, representing poor