Hot flushes occur in more than one half of women in the United States during the menopause transition1 and are severe enough to require treatment in about 20%.2 Estrogen is the most effective treatment for vasomotor symptoms,3 but is associated with increased risk for venous thromboembolism and stroke.4 The addition of a progestin to estrogen, as required in women with a uterus to prevent endometrial hyperplasia and cancer,5 increases risk for coronary events, stroke, breast cancer and venous thromboembolism.6 Given these increased risks, and other side effects such as uterine bleeding and breast tenderness, many women with hot flushes would like to avoid hormone therapy.
Some randomized trials have found that treatment with selective serotonin/norepinephrine reuptake inhibitors (SSRIs) is effective, but the evidence is mixed.7–12 Sertraline is less sedating than other SSRIs,13 and does not increase blood pressure, as can occur with venlafaxine1 (Effexor; Wyeth, Philadelphia PA). We performed a clinical trial to assess the effect of treatment with sertraline on the frequency and severity of hot flushes in healthy perimenopausal and postmenopausal women.
MATERIALS AND METHODS
The Flushes and Sertraline Trial was a randomized, blinded, placebo-controlled trial of the effect of sertraline on frequency and severity of hot flushes. Eligible women were generally healthy perimenopausal or postmenopausal women aged 40 to 60 years who reported experiencing at least 14 hot flushes per week and expressed willingness to take sertraline for treatment. Women with a history of breast or ovarian cancer, depression (Beck Depression Score more than 18 or suicidal ideation), chronic kidney or liver disease, bipolar affective disorder, seizures, and known hypersensitivity to sertraline or to selective serotonin reuptake inhibitors were excluded. Women taking drugs thought to be effective for treatment of hot flushes (estrogens, progestins, androgens, other selective serotonin reuptake inhibitors or gabapentin) and those taking drugs contraindicated with the use of sertraline were also excluded.
Participants were recruited using advertisements in newspapers and fliers posted in outpatient clinics at the University of California, San Francisco. All study measures were performed at the Women's Health Clinical Research Center of the University of California, San Francisco. The Committee on Human Research of the University of California, San Francisco approved the protocol and all participants provided written informed consent. Pfizer, Inc. provided an unrestricted grant and study medications to support this research. Employees of Pfizer did not participate in the design or conduct of the trial, analysis of data, or preparation of the manuscript.
Randomization was stratified by time since last menstrual period (1 year or less compared with more than 1 year). Within strata, treatment was assigned in randomly permuted blocks of randomly varied size 2 to 4 in a 1:1 ratio. A University of California, San Francisco pharmacist assigned eligible participants sequentially to the randomly assigned treatment.
We chose to use the highest dose of sertraline that is in widespread clinical use for treatment of depression (100 mg per day), and to increase the dose over a 2-week period as is commonly done in clinical practice. Participants received sertraline 50 mg orally (or identical placebo) daily for 2 weeks. If this dose was not associated with significant side effects after 2 weeks, the dose was increased to two tablets daily (100 mg of sertraline or identical placebo) and continued for an additional 4 weeks. All investigators, study staff and participants were blinded to study medication status until the trial was completed and the database was edited and locked.
At baseline, participants completed questionnaires regarding demographics; medical, gynecologic, menstrual, and hot flush history; smoking and alcohol use; medications; quality of life (Medical Outcomes Study [MOS] Short Form 3615); menopausal symptoms (Greene Climacteric Scale16); sleep quality (Pittsburgh Sleep Quality Index17); sexual function (Female Sexual Function Index18); and mood (Positive and Negative Affect Scale19).
Hot flush frequency and severity were recorded on a daily diary.20 The diary was completed during the 7 days before randomization, before increasing the dose of study medication (2nd week of treatment) and before the completion of the trial (6th week of treatment). For each hot flush, severity was rated as 1 (mild), 2 (moderate), 3 (severe), or 4 (very severe). The mean daily hot flush score was calculated as the sum of severity scores for all hot flushes divided by the number of reported flushes. At each follow-up visit (2 weeks and 6 weeks of treatment), study pills were counted and adverse effects recorded.
The primary outcomes of the trial were percentage change in mean daily hot flush frequency and score from baseline to 6 weeks of treatment. Secondary outcomes included change on scores for quality of life, menopausal symptoms, sleep quality, sexual function, mood, and side effects.
The total sample size of 100 was calculated to provide 80% power with two-tailed alpha .05 to detect a between-group difference of 20 percentage points in the percent change in hot flush frequency from baseline to 6 weeks. Change since baseline was assumed to depend on treatment, but not on the baseline value, and to have roughly constant standard deviation of 35% across baseline levels.21
We confirmed the approximate normality of the primary outcomes using quantile-quantile plots.22 All primary analyses were by intention to treat, according to randomized assignment and without regard to adherence. In the primary analysis, mean percent changes were compared using t tests. We conducted secondary analyses restricting the sample to women in each group who were at least 80% adherent to treatment as assessed by pill count. We also conducted linear regression analyses to adjust between-group comparisons for baseline variables including age, race or ethnicity, education, and years since menopause that were imperfectly balanced at baseline.
Between February 2004 and October 2005, 738 women were screened for eligibility. Of these, 433 declined to participate and 206 were not eligible. Of the 99 eligible women who were randomly assigned, 49 were assigned to placebo and 50 to sertraline (Fig. 1). Of these, 44 women in the placebo group and 45 in the sertraline group completed the trial. Among women completing the trial, 37 in the placebo group and 37 in the sertraline group took at least 80% of study medication, based on pill counts. All of the women assigned to sertraline and 47 of the 49 assigned to placebo increased the dose from 50 mg to 100 mg after 2 weeks of treatment. At the end of the trial, 29 women in the sertraline group and 31 in the placebo group correctly guessed their treatment assignment (κ=0.35).
The average age of participants was 52 years, and 57% were white. The treatment groups were comparable at baseline except that women randomly assigned to sertraline were somewhat younger, and a higher proportion were African American and less educated than women randomly assigned to placebo (Table 1). The mean number of hot flushes per day at baseline was 9.3 (±7.2) in the placebo group and 8.6 (±4.4) in the sertraline group (Table 2). Hot flushes improved during treatment in both groups (Fig. 2). At week 2 of treatment, the frequency of daily hot flushes was reduced 19% in the placebo group and 22% in the sertraline group (P=.63); at week 6, the frequency of hot flushes was reduced 38% in placebo and 39% in sertraline (between-group difference at 6 weeks 0.7%, 95% confidence interval [CI] –15.9 to 17.2%; P=.94). The mean hot flush score also improved during treatment, with no significant difference between treatment groups (between-group difference at 6 weeks 1.6%, 95% CI –16.4 to 19.6%, P=.86; Fig. 2 and Table 2). Analyses restricted to women in both treatment groups who were at least 80% adherent to assigned study medication yielded similar results.
There was no association of baseline age, ethnicity, education, or years since menopause with improvement in hot flush frequency or score. Treatment with sertraline was not associated with improvement in hot flush frequency (P=.91) or hot flush score (P=.65) in multivariable linear regression analyses adjusted for age, ethnicity, education, and years since menopause.
Compared with placebo, treatment with sertraline resulted in greater worsening of scores on the Medical Outcomes Study (MOS) Short Form 36 standardized physical component, the global Female Sexual Function Index, and subscales of the Female Sexual Function Index, including arousal, lubrication, orgasm, satisfaction, and pain (Table 3). These findings were unchanged in analyses restricted to women who were at least 80% adherent to study medication, and persisted after adjustment for baseline age, ethnicity, education, and years since menopause. There was no interaction of treatment effect and years since menopause.
Adverse events reported by four or more participants in either group are described in Table 4. Compared with placebo, women in the sertraline group were more likely to report dry mouth.
In this randomized, blinded, placebo-controlled trial, treatment with 50 mg of sertraline daily for 2 weeks followed by 100 mg daily for 4 weeks did not improve the frequency or severity of hot flushes among perimenopausal and postmenopausal women with frequent hot flushes. In these generally healthy women, treatment with sertraline was associated with a decrement in the physical component of quality of life, worsened sexual function, and dry mouth. The between-group difference in percent change in frequency of hot flushes of 0.7% and 95% CI of –15.9 to 17.2% (P=.94) suggests that treatment with sertraline is unlikely to be more than 16% better than placebo, a potential benefit that we do not believe is worthwhile given the adverse effects associated with treatment.
Sertraline is an SSRI with demonstrated benefit for treatment of depression and other mood disorders. Sertraline has an excellent reported side effect profile in these patients, causing less sedation than most other drugs in this class.13 In a prior clinical trial, 62 women with localized breast cancer who were taking tamoxifen and reported at least one hot flush per day were randomly assigned to sertraline 50 mg per day or placebo for 6 weeks, then crossed over to the opposite treatment for an additional 6 weeks. There was no significant difference between the treatment groups in change in hot flush frequency or score at 6 weeks and no difference over the entire 12 weeks of treatment.23 Our results support this null finding.
The results of eight randomized, placebo-controlled trials of treatment with SSRIs for hot flushes are described in Table 5. Five of these trials (present study included) were parallel-group randomized trials,7,10–12 whereas three used a crossover design.8,9,23 All used daily hot flush diaries to record frequency or severity of hot flushes or both. Four trials included primarily breast cancer survivors,8–10,23 whereas participants in the remaining 4 trials were essentially healthy.
The main findings of these eight clinical trials are heterogeneous (P value for heterogeneity .008 using metan program from Stata 9.2 [StataCorp LP, College Station, TX]). Three of the four trials that were conducted primarily among breast cancer survivors demonstrated a statistically significant benefit of treatment, ranging from a 24% to 34% greater improvement in hot flush score among women treated with an SSRI compared with placebo.8–10 In contrast, three (present study included) of the four trials that included primarily women without a history of breast cancer found no improvement in hot flush score.11,12 The only SSRI with consistent evidence of efficacy among women both with and without a history of breast cancer is paroxetine, where the improvement was 25% to 30% better than placebo.7,8
It is not entirely clear why the efficacy of SSRIs for treatment of hot flushes might differ depending on whether most participants had a history of breast cancer. Because chemotherapy or oophorectomy for treatment of breast cancer often results in ovarian failure, menopause may have been more recent in women with a breast cancer. Use of tamoxifen, which can cause hot flushes, was common among participants in the trials that included mostly breast cancer survivors. It is possible that the mechanism of drug-induced hot flushes differs from hot flushes related to natural menopause. Selective serotonin reuptake inhibitors speed the metabolism of tamoxifen to inactive metabolites,24 possibly reducing the severity of side effects, including hot flushes. The proportion of participants who were depressed at baseline was between 20% and 54% among participants in the trials that included mostly breast cancer survivors.8–10,23 Although it is possible that improvement in depression due to treatment with SSRIs might make hot flushes less bothersome, baseline depression scores were not associated with treatment-related improvement of hot flushes in several studies.8–10
Treatment with sertraline did not improve the frequency or severity of hot flushes in generally healthy perimenopausal and postmenopausal women, but was associated with bothersome side effects. Selective serotonin reuptake inhibitors seem to have modest efficacy for treatment of hot flushes in women with a history of breast cancer but are not effective in women without this history. Future trials should be conducted in both groups of women to evaluate efficacy.
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