Use of Antidepressants for Management of Hot Flashes

Dana G. Carroll, Pharm.D.; Kristi W. Kelley, Pharm.D.

Pharmacotherapy. 2009;29(11):1357-1374.

Abstract and Introduction

Abstract

A growing body of evidence suggests that antidepressant therapies, particularly selective serotonin reuptake inhibitors and venlafaxine, are effective in the management of hot flash symptoms. Several of these agents have the support of the American College of Obstetricians and Gynecologists and the North American Menopause Society. To review the literature on antidepressants for the treatment of hot flashes in women, we searched the PubMed, International Pharmaceutical Abstracts, and MEDLINE databases from inception through May 2009. All publication types that included human participants and that were published in English were eligible for review. These articles, relevant abstracts, and additional references were used to collect pertinent data. Although initial small pilot trials were conducted solely in breast cancer survivors, additional studies have been conducted both in breast cancer survivors and in relatively healthy menopausal women. Data on the benefits with many of these agents are conflicting. Venlafaxine and paroxetine have been studied more extensively than any of the other antidepressants and are more consistent in effectively reducing the frequency and severity of hot flashes, based on these study results. Desvenlafaxine, sertraline, fluoxetine, and citalopram should be considered second- or third-line options if patients fail therapy with or cannot tolerate venlafaxine or paroxetine, based on the current published data. Duloxetine, escitalopram, fluvoxamine, and mirtazapine should be reserved as last-line therapy until more rigorous studies are conducted assessing their use in the management of hot flashes.

Introduction

The Women's Health Initiative study^[1] caused many health care providers and menopausal women to reconsider use of hormonal agents. The study was stopped early because researchers found increased rates of breast cancer (number needed to harm [NNH] 1250], coronary artery disease (NNH 1428), stroke (NNH 1250), and pulmonary embolism (NNH 1250) in women treated with conjugated equine estrogen plus medroxyprogesterone compared with placebo. Many women and their physicians are now seeking nonhormonal therapies for the management of hot flash symptoms. During the last 8 years, a growing body of evidence has suggested that antidepressant therapies, particularly selective serotonin reuptake inhibitors (SSRIs) and venlafaxine, are effective in the management of hot flash symptoms. Several of these therapies have the support of the American College of Obstetricians and Gynecologists and the North American Menopause Society.^[2,3] The initial trials were conducted in breast cancer survivors, and this had resulted in many health care professionals questioning how and if we could extrapolate the data to relatively healthy menopausal woman. However, additional studies have been conducted both in breast cancer survivors and in relatively healthy menopausal women.

We conducted a literature search of the PubMed, International Pharmaceutical Abstracts, and MEDLINE databases from inception through May 2009 by combining the term "hot flash" individually with venlafaxine, desvenlafaxine, duloxetine, paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram, escitalopram, and mirtazapine. All publication types that included human participants and that were published in English were eligible for review. These articles, relevant abstracts, and additional references were used to collect pertinent data. In this review, we evaluate the published literature on the use of antidepressants for the management of hot flash symptoms.

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Abstract and Introduction
Pathophysiology of Hot Flashes
Evaluation of Hot Flashes in Clinical Trials
Overview of Current Literature
Comparison with Other Agents
Recommendations
Conclusion
References

Table 1. Common Validated Instruments Used to Assess Hot Flashes and Menopausal Symptoms
Instrument	Score Calculation	Score Interpretation
Hot Flash Score^[8]	Severity score = (number of mild hot flashes/day × 1) + (number of moderate hot flashes/day × 2) + (number of severe hot flashes/day × 3) + (number of very severe hot flashes/day × 4)/total number of hot flashes/day Some trial methodologies deviate from this formula slightly, excluding hot flashes in the very severe category and including them in the severe category	Higher scores indicate worse symptoms There is no maximum score since the score is patient dependent for both number and severity
Greene Climacteric Score^[9]	Assesses four subcomponents of both symptoms and quality of life: psychological (possible score 0-33), somatic (0-21), vasomotor symptoms (0-6), and sexual (0-3)	Total score can range from 0-63 Higher scores indicate worse symptoms For the vasomotor subscore, a score of 0-2 indicates no or mild hot flashes and 3-6 indicates moderate-to-severe hot flashes
Modified Kupperman Index^[10]	Assesses 11 subcomponents: hot flashes, sweating, insomnia, nervousness, depression, vertigo, tiredness, joint ache, headache, palpitations, and vaginal dryness All are scored from 0-3 based on symptoms: 0 = none, 1 = weak, 2 = moderate, 3 = strong Hot flash score is multiplied by 4; sweating, insomnia, and nervousness scores are multiplied by 2; then all subcomponents are added together for the total score	Total score can range from 0-51 Higher scores indicate worse symptoms

Table 2. Studies of Common Therapies Used to Treat Hot Flashes
Drug	Total Daily Dose	Results	Common Adverse Effects
Venlafaxine^{[14,15,16,17,18,19,20]}	37.5-150 mg	Hot flash score decreased 37-61% Hot flash frequency decreased 30-58%	Decreased appetite, anxiety, constipation, dry mouth, and nausea
Paroxetine^[26]	10-20 mg	Hot flash score decreased 28.6-31.9% Hot flash frequency decreased 25.2-27%	Headache, nausea, somnolence, insomnia, dry mouth
Paroxetine CR^[25,27]	2.5-25 mg	Hot flash score decreased 62-65%	Headache, nausea, somnolence, insomnia, dry mouth
Gabapentin^{[44,45,46,47]}	300-2400 mg	Hot flash score decreased 31-71% Hot flash frequency decreased 45-49%	Somnolence, fatigue, dizziness, rash
Hormone replacement therapy^[51]	Various	Number of hot flashes decreased ~18/wk Hot flash frequency decreased ~75%	Nausea, breast tenderness, atypical uterine bleeding, bloating, perception of weight gain
Soy^{[48,49,50,52]}	33-120 mg (of isoflavones)	Hot flash frequency decreased 61-74%	Constipation, diarrhea, bloating, nausea, insomnia
Black cohosh^[30,53]	40 mg	Hot flash score decreased 85%	Gastrointestinal upset, rash, headache, dizziness, weight gain, feeling of heaviness in the legs, cramping, breast tenderness, vaginal spotting or bleeding, liver toxicity
CR = controlled release.

Table 3. Summary of the Literature on Antidepressants for Treatment of Hot Flashes
Study Design	Patient Characteristics	Treatment Regimen	Study Duration	Outcomes	Results
Venlafaxine
Open-label (n=28)^[13]	Men taking androgen deprivation therapy (18%) and women with history of breast cancer (82%); 89% ≥ age 50 yrs; 90% had > 4 hot flashes/day; 68% taking tamoxifen	Venlafaxine 12.5 mg b.i.d.	4 wks	Hot flash score, number of hot flashes	Mean changes in hot flash scores NR Mean number of hot flashes decreased by 2.3/day
Randomized, double-blind, placebo-controlled (n=229)^[14]	History of breast cancer or fearful of getting breast cancer from ERT or HRT use (% with history of breast cancer NR); mean age NR; mean of 8 hot flashes/day; 69% taking tamoxifen or raloxifene	Venlafaxine 37.5, 75, or 150 mg q.d. vs placebo	4 wks	Number of hot flashes, hot flash score	Median decrease in frequency of hot flashes: 19% (placebo), 30% (37.5 mg), 46% (75 mg), 58% (150 mg) Median decrease in hot flash score: 27% (placebo), 37% (37.5 mg), 61% (both 75 mg and 150 mg)
Open-label (n=102)^[15] (continuation of above study^[14])	History of breast cancer or fearful of getting breast cancer from ERT or HRT use (% with history of breast cancer NR); mean age 53 yrs; 91% had ≥ 4 hot flashes/day; 66% taking tamoxifen or raloxifene	Venlafaxine 37.5, 75, or 150 mg q.d.	8 wks	Number of hot flashes, hot flash score	Maintained response in initial study^[14] in the 75- and 150-mg/day groups Patients previously taking placebo had a 62% mean decrease in hot flash scores Patients taking 37.5 mg/day had an additional 26% mean decrease in hot flash scores
Double-blind, placebo-controlled, crossover (n=70)^[16]	History of breast cancer; mean age 50.5 yrs(37.5 mg), 53.0 yrs (75 mg); mean of 7.46 hot flashes/day; 51% (37.5 mg), 63% (75 mg) taking tamoxifen or an aromatase inhibitor	Venlafaxine 37.5 or 75 mg q.d. vs placebo	12 wks (6 wks active treatment)	24-hr sternal skin conductance, number of hot flashes, self-reported number of hot flashes	Mean decrease in frequency from baseline: 37.5 mg/day: 22% with sternal monitoring, 42% self-reported (p<0.001); 75 mg/day: 14% with sternal monitoring, 25% self-reported (p=0.013)
Double-blind, crossover (n=64)^[17]	History of breast cancer; 61% > age 50 yrs; mean hot flashes/day: 9.9 (clonidine), 10.9 (venlafaxine); 82% (clonidine) and 90% (venlafaxine) taking tamoxifen or aromatase inhibitor	Venlafaxine 37.5 mg b.i.d. vs clonidine 0.075 mg b.i.d.	8 wks (4 wks in each arm)	Number of hot flashes, hot flash score	Median hot flash frequency decreased by 7.6 hot flashes/day (57%) with venlafaxine and by 4.85 hot flashes/day (37%) with clonidine (p=0.025) Median hot flash scores decreased by 11.4 units/day (57%) with venlafaxine and by 8.9 units/day (39%) with by 8.9 units/day (39%) with clonidine (p=0.043)
Randomized, controlled (n=218)^[18]	History of breast cancer or fearful of getting breast cancer from ERT or HRT use (61% history of breast cancer); mean age 55 yrs; 90% had ≥ 4 hot flashes/day; 41% taking tamoxifen or raloxifene	Venlafaxine 37.5 mg q.d. × 1 wk then 75 mg q.d. vs MPA 400 mg i.m. × 1	6 wks	Number of hot flashes, hot flash score	Actual changes in hot flash frequency NR Hot flash scores decreased 79% with MPA vs 55% with venlafaxine (p<0.0001)
Randomized, double-blind, placebo-controlled (n=80)^[19]	Relatively healthy, menopausal women; mean age: 51.6 yrs (placebo), 52.7 yrs (venlafaxine); mean hot flashes/day and hot flash score NR in text (graphs provided); mean yrs since menopause: 4.0 (placebo), 4.9 (venlafaxine); surgical menopause: 22.5% (placebo), 18.9% (venlafaxine)	Venlafaxine extended release 37.5 mg q.d. × 1 wk then 75 mg q.d vs placebo	12 wks	Hot flash score	Hot flash scores decreased by 51% in venlafaxine group vs 15% in placebo group (p<0.001) at 12 wks
Open-label (n=14)^[20]	Menopausal women with depressive disorder; mean age 45.9 yrs; mean hot flashes/day NR; mean GCS vasomotor score 1.6; mean yrs since menopause and % surgical menopause NR	Venlafaxine 37.5 mg q.d. × 1 wk then 75 mg q.d. with optional dosage increase	8 wks	HAM-D and GCS scores	GCS vasomotor subscores were not significantly different from baseline Vasomotor symptoms were not required for study entry
Desvenlafaxine
Randomized, double-blind, placebo-controlled (n=707)^[21]	Relatively healthy, menopausal women; mean age: 54 yrs (placebo), 53 yrs (all desvenlafaxine groups); mean number of moderate-to-severe hot flashes/day: 10.8 (50 mg), 10.5 (100 mg), 11.2 (150 mg), 11.1 (200 mg), 11.0 (placebo); mean yrs since surgical/natural menopause: 8/4.4 (50 mg), 10.8/4.2 (100 mg), 11.0/4.4 (150 mg), 13.1/4.9 (200 mg), 11.2/6.4 (placebo); surgical menopause: 21.3% (50 mg), 20.7% (100 mg), 22.6% (150 mg), 21.7% (200 mg), 23.4% (placebo)	Desvenlafaxine 50, 100, 150, or 200 mg q.d. vs placebo	52 wks	Number of moderate-to-severe hot flashes, hot flash score	Hot flash frequency decreased by 51-64% in all groups at wk 12; the 100- and 150-mg groups had significantly greater decreases in hot flashes/day vs placebo at wk 12: 7.23/day (p=0.005) and 6.94/day (p=0.020), respectively, vs 5.50/day Hot flash score decreased from baseline in all 5 groups at wk 12; the 100- and 200-mg groups were significantly better vs placebo in hot flash score reductions: 31% (p=0.002) and 27% (p=0.013), respectively, vs 18%; results beyond wk 12 NR
Duloxetine
Open-label (n=20)^[22]	Menopausal women with major depression; mean age 52.3 yrs; mean hot flashes/day NR; median GCS vasomotor score 5.0; mean yrs since menopause NR; 7% surgical menopause	Duloxetine 30 mg q.d. × 1 wk then 60 mg q.d. × 3 wks with optional dosage increase	8 wks	MADRS (primary) and GCS scores	Significant differences from baseline in total GCS score (p=0.0001) and GCS vasomotor subscore (p=0.003); actual scores NR
Paroxetine
Open-label (n=13)^[23]	History of breast cancer; mean age 51.6 yrs; mean hot flashes/day NR; mean hot flash severity score 3.62; 69% taking tamoxifen	Paroxetine 10 mg q.d. × 3 days then 20 mg q.d.	5 wks	Hot flash score	Significant decrease in hot flash score by 43% to 2.08 (p<0.002)
Open-label (n=30)^[24]	History of breast cancer; 73% ≥ age 50 yrs; 74% had ≥ 5 hot flashes/day, 80% taking tamoxifen	Paroxetine 10 mg q.d. × 1 wk then 20 mg q.d.	5 wks	Number of hot flashes/wk, hot flash score/wk	Significant decrease in hot flash score by 43% to 2.08 (p<0.002)
Randomized, double-blind, placebo-controlled, crossover (n=151)^[26]	Menopausal women with or without history of breast cancer (80% with history of breast cancer); median age 50-55 yrs across groups; mean hot flashes/day: 7.3 (paroxetine 10 mg/placebo), 6.9 (paroxetine 20 mg/placebo), 7.1 (placebo/paroxetine 10 mg), 7.8 (placebo/paroxetine 20 mg); > 60% taking tamoxifen or raloxifene	Paroxetine 10 or 20 mg q.d. vs placebo	8 wks (4 wks active treatment)	Number of hot flashes, hot flash score	Weekly hot flash frequency decreased by 67%, and hot flash score decreased by 75% compared with baseline (p values NR)
Paroxetine CR
Randomized, double-blind, placebo-controlled (n=165)^[25]	Menopausal women with or without history of breast cancer (7% with history of breast cancer); mean age: 53.6 yrs (12.5 mg), 55.0 yrs (25 mg), 53.6 yrs (placebo); mean hot flashes/day: 7.1 (12.5 mg), 6.4 (25 mg), 6.6 (placebo); mean yrs since menopause and % surgical menopause NR; use of tamoxifen and raloxifene: 2% (12.5 mg), 8.6% (25 mg), 10.8% (placebo)	Paroxetine CR 12.5 or 25 mg q.d. vs placebo	6 wks	Hot flash score	10-mg group: hot flash frequency significantly decreased by 27% (p=0.0006) and hot flash scores by 31.9% (p=0.0008) vs placebo 20-mg group: hot flash frequency significantly decreased by 25.2% (p=0.002) and hot flash scores by 28.6% (p<0.0001) vs placebo
Randomized, double-blind, placebo-controlled (n=56)^[27]	Relatively healthy, menopausal women; mean age: 57.0 yrs (placebo), 55.6 yrs (paroxetine); mean hot flashes/day NR; median GCS vasomotor score: 4.0 (placebo), 4.5 (paroxetine); mean yrs since menopause NR; surgical menopause: 32.2% (placebo), 28.5% (paroxetine)	Paroxetine CR 12.5 mg q.d. × 2 wk vs placebo; may increase to 25 mg q.d. if not efficacious and is well tolerated	6 wks	Number of hot flashes, GCS score	Significantly decreases in hot flash scores in both 12.5-mg and 25-mg groups vs placebo (62% and 65%, respectively, vs 37%, p<0.001)
Fluoxetine
Randomized, double-blind, placebo-controlled crossover (n=81)^[8]	History of breast cancer or fearful of getting breast cancer from ERT or HRT use (% history of breast cancer NR); age ≥ 50 yrs: 73% (placebo/fluoxetine), 75% (fluoxetine/placebo); mean of 7.9 hot flashes/day; taking tamoxifen: 56% (placebo/fluoxetine), 53% (fluoxetine/placebo)	Fluoxetine 20 mg q.d. vs placebo	8 wks (4 wks active treatment)	Number of hot flashes, hot flash score	Median hot flash frequency decreased by 6.2 in paroxetine group vs 2.8 in placebo group (p=0.03) GCS scores also significantly decreased (p=0.04); scores NR 63% increased paroxetine dose to 25 mg/day
Open-label (n=12)^[29]	History of breast cancer; mean age 47.9 yrs; mean of 8.8 hot flashes/day; mean hot flash score 27.1, 66% taking tamoxifen	Fluoxetine 10 mg q.d.	4 wks	Number of hot flashes, hot flash score	Fluoxetine was significantly better than placebo: median daily hot flashes decreased by 1.5 (19%, p=0.01), hot flash scores decreased by 3.1/day (24%, p=0.02)
Randomized, controlled (n=120)^[30]	Relatively healthy, menopausal women; mean age: 53.1 yrs (black cohosh), 52.7 yrs (fluoxetine); mean hot flashes/day NR; mean MKI score: 25.1 (black cohosh), 25.2 (fluoxetine); mean yrs since menopause and % surgical menopause NR	Fluoxetine 20 mg q.d. vs black cohosh 40 mg q.d.	6 mo	MKI and hot flash scores	Hot flash frequency decreased by 36% (p=0.001) and hot flash scores decreased by 46.2% (p=0.0006) compared with baseline MKI scores were significantly better with black cohosh than fluoxetine at 3 mo (mean ± SD 13.9 ± 19.1 vs 18.5 ± 5.9, p=0.002); MKI scores at 6 mo NR Hot flash scores were reduced more with black cohosh than fluoxetine (85% vs 62%, p<0.001)
Fluoxetine or citalopram
Randomized, double-blind, placebo-controlled (n=150)^[31]	Relatively healthy, menopausal women; mean age 54 yrs; mean hot flashes/day and KI scores NR in text (graphs provided); mean yrs since menopause and % surgical menopause NR	3 arms: fluoxetine, citalopram, placebo Fluoxetine and citalopram dosage: 10 mg q.d. × 1 mo, then 20 mg q.d. × 5 mo, then 30 mg q.d. × 3 mo	9 mo	KI score, number of hot flashes	All 3 groups had significantly improved hot flash frequency and KI scores from baseline (p<0.001 for all comparisons); no significant differences were noted between groups, including comparison with placebo
Sertraline
Randomized, double-blind, placebo-controlled, crossover (n=62)^[33]	History of breast cancer with depression; mean age 53.9 yrs; mean of 5.8 hot flashes/day; 100% taking tamoxifen	Sertraline 50 mg q.d. vs placebo	12 wks (6 wks active treatment)	Complete resolution of hot flashes in initial 6 wks (primary), hot flash score, number of hot flashes/wk	No patient experienced complete resolution of hot flashes in initial 6 wks After initial 6-wk phase, no significant differences were noted between groups in hot flash scores or frequency After second 6-wk phase, sertraline was significantly better than placebo in improving hot flash scores (−1.7 vs 3.2, p=0.03) and number of hot flashes/wk (−0.9 vs 1.5, p=0.03) Data were analyzed as 2 different treatment periods (initial 6 wks and second 6 wks); data for treatment and placebo arms were never pooled for analysis
Randomized, double-blind, placebo-controlled, crossover (n=97)^[34]	Relatively healthy, menopausal women; mean age 52.6 yrs, mean of 47.3 hot flashes/wk; mean yrs since menopause and % surgical menopause NR	Sertraline 50 mg q.d. vs placebo	9 wks (4 wks active treatment)	Number of hot flashes, severity of hot flashes, hot flash score	Weekly hot flash frequency decreased by 5 and was significantly better than placebo (p=0.002) Median hot flash scores decreased more in sertraline arm than placebo arm (48% vs 30%, p=0.001)
Randomized, double-blind, placebo-controlled, (n=99)^[35]	Relatively healthy, menopausal women; mean age: 52.6 yrs (placebo), 50.5 yrs (sertraline); mean hot flashes/day: 9.3 (placebo), 8.6 (sertraline); mean hot flash score: 18.4 (placebo), 16.4 (sertraline); mean yrs since menopause: 3.1 (placebo), 3.9 (sertraline); % surgical menopause NR	Sertraline 50 mg q.d. × 2 wks then 100 mg q.d. 4 wks vs placebo	6 wks	Number of hot flashes, hot flash score	No significant differences were noted between groups both in hot flash frequency and hot flash scores
Citalopram
Open-label (n=18)^[36]	History of breast cancer or fearful of getting breast cancer from ERT or HRT use (83% history of breast cancer); mean age NR; 72% had ≥ 4 hot flashes/day; 50% taking tamoxifen or aromatase inhibitor	Citalopram 10 mg q.d. × 1 wk then 20 mg q.d. × 3 wks	4 wks	Number of hot flashes, hot flash score	64% decrease in hot flash scores and 58% decrease in hot flash frequency compared with baseline
Open-label (n=22)^[37]	History of breast cancer or fearful of getting breast cancer from ERT or HRT use (90% breast cancer from ERT or HRT use (90% history of breast cancer) and failed venlafaxine therapy for hot flashes; median age 58 yrs, 100% had ≥ 4 hot flashes/day; 65.5% taking tamoxifen or aromatase inhibitor	Citalopram 10 mg q.d. × 1wk then 20 mg q.d. × 3 wks	4 wks	Number of hot flashes, hot flash score	Mean hot flash frequency decreased by 45% and hot flash scores decreased by 53% compared with baseline (p<0.001 for both comparisons)
Randomized, placebo-controlled (n=100)^[38]	Relatively healthy, postmenopausal women; mean age: 53.5 yrs (citalopram), 52.5 yrs (citalopram + HT), 51.7 yrs (placebo), 53.6 yrs (placebo + HT); mean hot flashes/day NR; MKI scores NR in text (graphs provided); mean yrs since menopause: 6.9 (citalopram), 7.3 (citalopram + HT), 6.1 (placebo), 6.0 (placebo + HT); % surgical menopause: 24% (citalopram), 32% (citalopram + HT), 24% (placebo), 12% (placebo + HT)	4 arms: citalopram, citalopram + HT, placebo, placebo + HT Citalopram dosage: 10 mg q.d. × 1 wk, then 20 mg q.d. × 3 wks; may increase to 40 mg q.d. × 4 wks if insufficient improvement	8 wks	MKI and hot flash scores	Mean hot flash and MKI scores significantly improved in all 4 groups compared with baseline; however, these scores were significantly better in the citalopram and citalopram + HT groups than in the placebo or placebo + HT groups (p<0.01 and p=0.001, respectively)
Escitalopram
Open-label (n=32)^[39]	Menopausal women with depression; mean age: 49 yrs (HT), 50 yrs (escitalopram); mean hot flashes/day NR; median total GCS score: 26.9 (HT), 28.7 (escitalopram); yrs since menopause and % surgical menopause NR	Escitalopram vs HT Escitalopram dosage: 10 mg q.d. × 4 wks; may increase to 20 mg q.d. if insufficient improvement	8 wks	MADRS (primary) and GCS scores	Median total GCS score decreased significantly more with escitalopram than HT (17.8 vs 8.75, p=0.01); vasomotor subscores were significantly different between therapies
Fluvoxamine Open-label (n=22)^[40]	Menopausal women with depression; mean age 52.9 yrs, mean hot flashes/day NR, mean SMI score 68.5, yrs since menopause and % surgical menopause NR	Fluvoxamine 50 mg q.d.	6 wks	SRQ-D (primary) and SMI scores	SMI scores decreased by 27% from baseline (p<0.05)
Randomized, controlled (n=42)^[41]	Menopausal women with depression and anxiety; mean age 48 yrs, mean hot flashes/day: 6.5 (HT), 6.7 (fluvoxamine + HT); yrs since menopause and % surgical menopause NR	Fluvoxamine 50 mg q.d. vs fluvoxamine 50 mg q.d. + HT	8 wks	SRQ-D score (primary), number of hot flashes	Both treatments significantly decreased the frequency of hot flashes from baseline; however, significantly fewer hot flashes were noted in the fluvoxamine + HT group than the fluvoxamine group (0.9 vs 1.8, p=0.036)
Mirtazapine
Open-label (n=22)^[4]	History of breast cancer or fearful of getting breast cancer from ERT or HRT use (59% history of breast cancer); mean age 56 yrs; 82% had ≥ 4 hot flashes/day; 54% taking tamoxifen or raloxifene	Mirtazapine 7.5 mg q.d. × 1 wk, then 15 mg q.d. × 1 wk, then 30 mg q.d. × 1 wk, then may continue at 30 mg q.d. or decrease to 15 mg q.d. × 1 wk	4 wks	Number of hot flashes, hot flash score	Median daily hot flashes decreased by 52.9% and median hot flash scores decreased by 59.5% from baseline
Open-label (n=27)^[43]	History of breast cancer; 45% aged > 50 yrs; 75% taking tamoxifen, raloxifene, or aromatase inhibitor	Mirtazapine 15 mg q.d. × 1 wk then 30 mg q.d.	12 wks	Number of hot flashes, hot flash score	Hot flash frequency decreased by 56.5% and hot flash scores decreased by 62.2% from baseline at wk 8 (p<0.05)

NR = not reported; ERT = estrogen replacement therapy; HRT = estrogen and progesterone replacement therapy; MPA = medroxyprogesterone acetate; MKI = Modified Kupperman Index; KI = Kupperman Index; HAM-D = Hamilton Depression Rating Scale; GCS = Greene Climacteric Scale; CR = controlled release; MADRS = Montgomery-Asberg Depression Rating Scale; HT = hormone therapy; SRQ-D = Self-Rating Questionnaire for Depression; SMI = Simple Menopausal Index.

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