Obstetrics & Gynecology:
Ineffectiveness of Sertraline for Treatment of Menopausal Hot Flushes: A Randomized Controlled Trial
Grady, Deborah MD, MPH1,2; Cohen, Beth MD1,2; Tice, Jeffrey MD1; Kristof, Margaret RN, MS1; Olyaie, Azin MS1; Sawaya, George F. MD1
From the 1University of California, San Francisco; and 2San Francisco VA Medical Center, San Francisco, California.
Study medication and partial funding provided by Pfizer.
Corresponding author: Deborah Grady, MD, MPH, UCSF Women's Health Clinical Research Center, 1635 Divisadero Street, Suite 600, San Francisco, CA 94115; e-mail: Deborah.Grady@ucsf.edu.
Financial Disclosure Dr. Grady received salary support through research contracts with Berlex, Inc., Wayne, NJ; Bionovo, Inc., Emeryville, CA; Eli Lilly and Company, Indianapolis, IN; and Pfizer, Inc., New York, NY.
OBJECTIVE: To estimate the effect of the selective serotonin reuptake inhibitor sertraline on hot flush frequency and severity in perimenopausal and postmenopausal women.
METHODS: We performed a randomized, blinded, placebo-controlled trial in women aged 40 to 60 years with 14 or more hot flushes per week (N=99). Women were randomly assigned initially to daily oral sertraline (50 mg) or identical placebo for 2 weeks. If no substantial side effects were noted, the dose was increased to two tablets daily (100 mg sertraline or placebo) and continued for an additional 4 weeks. Hot flush frequency and severity were recorded on a daily diary. Hot flush score was calculated as frequency multiplied by severity. Participants also completed questionnaires addressing quality of life, menopausal symptoms, sleep quality, sexual function, mood, and side effects.
RESULTS: After 6 weeks of treatment, hot flush frequency decreased similarly in both the placebo (38%) and sertraline (39%) groups (P=.94). Mean hot flush scores also decreased similarly in both groups (41% and 42%, respectively, P=.86). Compared with placebo, women in the sertraline group were more likely to report gastrointestinal complaints, dry mouth, and dizziness. Treatment with sertraline also resulted in greater worsening of scores on the Medical Outcomes Study (MOS) Short Form 36 standardized physical component and the global Female Sexual Function Index. Results were similar in women at least 80% adherent to study medication.
CONCLUSION: Treatment with sertraline did not improve hot flush frequency or severity in generally healthy perimenopausal and postmenopausal women, but was associated with bothersome side effects.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00283192
LEVEL OF EVIDENCE: I
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.
1. Gold EB, Sternfeld B, Kelsey JL, Brown C, Mouton C, Reame N, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol 2000;152:463–73.
2. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci. 1990;592:52–86.
3. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA 2004;291:1610–20.
4. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701–12.
5. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304–13.
6. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–33.
7. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003;289:2827–34.
8. Stearns V, Slack R, Greep N, Henry-Tilman R, Osborne M, Bunnell C, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 2005;23:6919–30.
9. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578–83.
10. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000;356:2059–63.
11. Suvanto-Luukkonen E, Koivunen R, Sundstrom H, Bloigu R, Karjalainen E, Haiva-Mallinen L, et al. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause 2005;12:18–26.
12. Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol 2005;105:161–6.
13. Whooley MA, Simon GE. Managing depression in medical outpatients. N Engl J Med 2000;343:1942–50.
14. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry 1998;59:502–8.
15. Ware JE Jr. SF-36 health survey update. Spine 2000;25:3130–9.
16. Greene JG. Constructing a standard climacteric scale. Maturitas 1998;29:25–31.
17. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213.
18. Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther 2000;26:191–208.
19. Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988;54:1063–70.
20. Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol 2001;19:4280–90.
21. Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. JAMA 2003;290:207–14.
22. Vittinghoff E, Glidden DV, Shiboski SC, McCulloch CE. Regression methods in biostatistics: linear, logistic, survival, and repeated measures models. New York (NY): Springer; 2005. p. 114–7.
23. Kimmick GG, Lovato J, McQuellon R, Robinson E, Muss HB. Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Breast J 2006;12:114–22.
24. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003;95:1758–64.
This article has been cited 27 time(s).
Journal of Sexual MedicineAndrogen Deprivation Therapy Impact on Quality of Life and Cardiovascular Health, Monitoring Therapeutic ReplacementJournal of Sexual Medicine
Psycho-OncologieAntidepressants in oncology: specificity's and particularitiesPsycho-Oncologie
Psychological BulletinHot flashes and panic attacks: A comparison of symptomatology, neurobiology, treatment, and a role for cognitionPsychological Bulletin
Archives of Womens Mental HealthUnderstanding the pathophysiology of vasomotor symptoms (hot flushes and night sweats) that occur in perimenopause, menopause, and postmenopause life stagesArchives of Womens Mental Health
American Journal of Obstetrics and GynecologyDesvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safetyAmerican Journal of Obstetrics and Gynecology
International Journal of Clinical PracticeMissed symptoms of menopauseInternational Journal of Clinical Practice
Breast Cancer Research and TreatmentThe efficacy of sertraline for controlling hot flashes in women with or at high risk of developing breast cancerBreast Cancer Research and Treatment
Journal of Clinical OncologyPhase III, Randomized, Double-Blind, Placebo-Controlled Evaluation of Pregabalin for Alleviating Hot Flashes, N07C1Journal of Clinical Oncology
Symptom management in premenopausal patients with breast cancer
Lancet Oncology, 9():
Journal of Clinical OncologyNewer Antidepressants and Gabapentin for Hot Flashes: An Individual Patient Pooled AnalysisJournal of Clinical Oncology
Journal of Womens Health
Ineffectiveness of sertraline for treatment of menopausal hot flushes: A randomized controlled trial
Journal of Womens Health, 16(6):
MaturitasThe menopause and oral healthMaturitas
Current Neurology and Neuroscience ReportsSleep and menopauseCurrent Neurology and Neuroscience Reports
Critical Reviews in Oncology HematologyManagement of complications of androgen deprivation therapy in the older manCritical Reviews in Oncology Hematology
Zdravniski Vestnik-Slovenian Medical Journal
Treatment Possibilities of Menopausal Symptoms in Breast Cancer Patients
Zdravniski Vestnik-Slovenian Medical Journal, 78():
ClimactericWhat can be done about hot flushes after treatment for breast cancer?Climacteric
Expert Opinion on Investigational DrugsMenopausal hormone therapy for vasomotor symptoms: balancing the risks and benefits with ultra-low doses of estrogenExpert Opinion on Investigational Drugs
Annals of OncologyPractical clinical guidelines for assessing and managing menopausal symptoms after breast cancerAnnals of Oncology
Actas Espanolas De Psiquiatria
Treatment with venlafaxine extended release for climacteric women with depression or anxiety diagnosis. An open-label study
Actas Espanolas De Psiquiatria, 37(3):
Annals of Clinical Psychiatry
Escitalopram reduces hot flashes in nondepressed menopausal women: A pilot study
Annals of Clinical Psychiatry, 21(2):
Use of Antidepressants for Management of Hot Flashes
Hematology-Oncology Clinics of North AmericaBreast Cancer Survivorship IssuesHematology-Oncology Clinics of North America
MenopauseSSRIs for menopausal hot flashes: a promise yet to be deliveredMenopause
Clinical Obstetrics and GynecologySymptoms of Menopause: Hot FlushesClinical Obstetrics and Gynecology
MenopauseIs a shorter hot flash diary just as good as a 7-day diary?Menopause
© 2007 by The American College of Obstetricians and Gynecologists.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Looking for ABOG articles? Visit our ABOG MOC II collection. The selected Green Journal articles are free through the end of the calendar year.
ACOG MEMBER SUBSCRIPTION ACCESS
If you are an ACOG Fellow and have not logged in or registered to Obstetrics & Gynecology, please follow these step-by-step instructions to access journal content with your member subscription.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read