Use of Antidepressants for Management of Hot Flashes

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

Disclosures

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

In This Article

Overview of Current Literature

Serotonin-norepinephrine Reuptake Inhibitors

Venlafaxine, desvenlafaxine, and duloxetine are antidepressants belonging to a class called serotonin-norepinephrine reuptake inhibitors (SNRIs). These agents have potent inhibitory effects on serotonin and norepinephrine reuptake, as well as weak inhibition of dopamine reuptake. Inhibition of serotonin reuptake occurs regardless of the dose. However, inhibition of norepinephrine increases as the dose increases.[11,12] Among these three agents, venlafaxine has been studied the most for treatment of hot flashes.[13,14,15,16,17,18,19,20]

Venlafaxine Venlafaxine has demonstrated efficacy in relieving hot flashes in women with and those without a history of breast cancer.[13,14,15,16,17,18,19,20] An initial pilot study[13] that showed benefit from low-dose venlafaxine prompted further study in a 4-week, randomized, controlled trial in 229 breast cancer survivors or women who were fearful of developing breast cancer from estrogen use.[14] Women had to have at least 14 hot flashes/week to be eligible for enrollment. Significant changes were noted in median hot flashes (frequency and scores) with all three doses of venlafaxine 37.5, 75, and 150 mg/day compared with placebo (p<0.001). From baseline to week 4, the median number of hot flashes decreased by 19% in the placebo group, 30% in the 37.5-mg/day group, 46% in the 75-mg/day group, and 58% in the 150-mg/day group. The hot flash scores decreased by 27% in the placebo group, 37% in the 37.5-mg/day group, and 61% in both the 75- and 150-mg/day groups. This study was continued as an open-label study.[15] One hundred two women elected to participate in an 8-week continuation phase. Participants who had been receiving 75 or 150 mg/day maintained their initial responses, and in those patients who were receiving 37.5 mg/day or placebo, the doses were titrated to an effective dose. Participants who began to receive venlafaxine in this continuation study (previously receiving placebo) experienced a 62% mean decrease in hot flash scores compared with baseline. Patients initially randomized to 37.5 mg/day were allowed to increase their dose to either 75 or 150 mg/day. Those who continued with 37.5 mg/day because of initial good response experienced an additional 26% mean decrease in hot flash scores. Of those who dose was titrated to 75 or 150 mg, the hot flash score reductions were similar (~33%) regardless of dose.

There were several limitations to these two trials.[14,15] The study population was primarily breast cancer survivors, which limits generalized application of the results. Tamoxifen and raloxifene were allowed, with 69%[14] and 66%[15] taking these therapies. Since use of these agents could increase the frequency and severity of symptoms, it may result in a greater response to therapy. The initial randomized controlled trial was of short duration, and the open-label continuation trial allowed for greater bias.

Three more recently published studies assessed venlafaxine in breast cancer survivors.[16,17,18] A 12-week crossover study was conducted in 70 women who had been experiencing at least 7 hot flashes/week.[16] Women were randomly assigned to venlafaxine 37.5 or 75 mg/day or placebo. Physiologic and self-reported hot flashes significantly improved in both venlafaxine groups compared with baseline and with the placebo group. Women receiving 37.5 mg/day experienced a 22% decrease in physiologic hot flashes recorded and a 42% decrease in selfreported hot flashes from baseline, which was significant (p<0.001) compared with placebo. Women receiving 75 mg/day experienced a 14% decrease physiologically in hot flashes and a 25% (p=0.013) decrease in self-reported hot flashes from baseline, which was significant (p<0.001) compared with placebo. Severity also improved significantly in both treatment groups compared with placebo and baseline (p<0.001). Strengths of this trial include its crossover design and physiologic measuring of hot flashes to minimize patient subjectivity in reporting hot flashes. The results are limited by applicability to breast cancer survivors. Most patients were Caucasian (90%), which is typical for most hot flash studies. This too could limit applicability of results. Also, this trial was of short duration.

The other two studies compared venlafaxine with active treatments. An 8-week crossover study assessed 64 breast cancer survivors who were experiencing hot flashes at least 14 times/week.[17] The study compared venlafaxine with oral clonidine. Venlafaxine 37.5 mg twice/day was significantly better (p=0.025) at decreasing median hot flash frequency (decrease of 7.6 hot flashes/day [57%]) compared with oral clonidine 0.075 mg twice/day (4.85 hot flashes/day [37%]). For the secondary end point, median hot flash scores also decreased in favor of venlafaxine (57% vs 39%, p=0.043). There were several limitations to this trial. The study has limited application because of the study population. Eighty-six percent (55 patients) were receiving either tamoxifen and/or another endocrine agent, which could affect the response to therapy as previously discussed. As before, this trial was of short duration.

A randomized controlled trial assessed 218 women with or without a history of breast cancer who were having at least 14 hot flashes/week.[18] Women were randomly assigned to either one intramuscular injection of medroxyprogesterone acetate 400 mg or venlafaxine 37.5 mg/day for 1 week followed by 75 mg/day for 5 weeks. Although medroxyprogesterone is not standard of care for hot flash management in the general population, it had been used in breast cancer survivors to manage hot flash symptoms with success before this study was conducted. When compared with medroxyprogesterone, venlafaxine 75 mg/day was not as effective in reducing hot flash scores (55% vs 79%, p<0.0001). However, hot flash scores did significantly decrease from baseline for the venlafaxine group. This trial's primary outcome was to assess the frequency of hot flashes. However, the authors failed to report actual results of this outcome for either group.

The first randomized controlled trial of venlafaxine was conducted in 80 menopausal women without a history of breast cancer.[19] To be eligible for this trial, women had to experience at least 14 hot flashes/week. Women were randomly assigned to receive either venlafaxine extended release 37.5 mg/day for 1 week followed by 75 mg/day for 11 weeks or placebo. Mean hot flash scores substantially declined in both groups at week 4, and no significant differences were noted between the groups. By week 12, hot flash scores had decreased significantly more with venlafaxine 75 mg/day than with placebo (51% vs 15%, p<0.001). The results of this trial have more generalized application given that the study population was relatively healthy menopausal women and only 42% were Caucasian. In addition, a strength of this trial was its longer duration.

Finally, an open-label study evaluated the efficacy of venlafaxine in 14 menopausal women with depression.[20] This study reported no significant decreases in GCS vasomotor subscores compared with baseline in women taking venlafaxine 75 mg/day. However, these results may be misleading because women did not have to have vasomotor symptoms for study entry. This trial is limited by its open-label design, short duration, and small sample size. In addition, this trial was not designed to specifically assess vasomotor symptoms. Changes in GCS scores appeared to be a secondary outcome, although the authors never clearly stated this.

Although venlafaxine's antidepressant effects may take 4-8 weeks to peak,[10] its ability to relieve hot flashes may be observed within 1-2 weeks of starting therapy.[17,18,19] The greatest efficacy in hot flash relief appears to occur with venlafaxine 75 mg/day, with no additional benefit at higher doses.[14] Since some patients may receive benefit from venlafaxine 37.5 mg/day, it may be best to start at 37.5 mg/day and increase to 75 mg/day if patients do not receive relief after 1-2 weeks. Adverse effects occurring more frequently compared with placebo or other active treatments in venlafaxine trials for hot flashes included decreased appetite, anxiety, constipation, dry mouth, and nausea. The frequency of dry mouth appeared to be greatest at 150 mg/day.[14,15]

Desvenlafaxine A randomized controlled trial of desvenlafaxine was conducted in 707 healthy, menopausal women without a history of breast cancer.[21] To be eligible for this trial, women had to experience at least seven moderate-to-severe hot flashes/day. Women were randomly assigned to receive either desvenlafaxine 50, 100, 150, or 200 mg/day or placebo for 52 weeks. All five groups had significant changes in the number of moderate-to-severe hot flashes from baseline, ranging 51-64% at week 12. The 100-mg/day group was the only desvenlafaxine group that was significantly different from placebo at week 12 (−7.23 vs −5.50 hot flashes/day, p=0.005). Mean hot flash scores declined in all groups at week 12 compared with baseline, but no significant differences were noted between any of the groups, including the placebo group.

A strength of this study was that it was conducted primarily in women who had undergone natural menopause (69%) and who had no history of breast cancer. Natural menopause is associated with less severe hot flash symptoms (frequency and severity) than is chemotherapy- or drug-induced or surgical menopause. One significant limitation of this trial is that the authors did not report the results beyond 12 weeks, even though this trial was 52 weeks in duration. Another limitation is the dropout rate. Seventy-three percent (519 patients) completed the trial at 12 weeks, whereas only 52% (368 patients) completed the trial to week 50.

Although desvenlafaxine's antidepressant effects may take weeks to peak, its ability to relieve hot flashes may be observed within 1-2 weeks of starting therapy. The greatest efficacy in hot flash relief appears to occur after 4 weeks of therapy.[21] Desvenlafaxine 100 mg/day is most effective for hot flash relief,[21] and there appears to be no additional benefit with higher doses. Since some patients may receive benefit from lower doses, it may be best to start at 50 mg/day and increase to 100 mg/day if patients do not receive relief after a few weeks. Adverse effects that occurred more frequently with desvenlafaxine than with placebo included increased blood pressure, decreased appetite, dry mouth, and nausea, and the frequency of adverse effects appeared to be greatest at higher doses (> 100 mg/day).[21]

Duloxetine An open-label trial with duloxetine was conducted in 20 menopausal women with major depressive disorder.[22] Women had to experience at least 14 hot flashes/week or have a GCS vasomotor subscale score higher than 3 or a GCS overall score of 20 or higher. Twenty women met inclusion criteria, yet only 14 completed the study. Treatment began with duloxetine 30 mg/day for 1 week and then increased to 60 mg/day for 3 weeks. If the patient remained symptomatic after 4 weeks, the dose could be increased further. The mean ± SD dose was 80 ± 18.5 mg at the end of the 8-week trial. The primary outcome for this trial was change in the Montgomery-Asberg Depression Rating Scale (MADRS), and the secondary outcome was change in vasomotor symptoms. The authors reported that there were significant differences in the total GCS score (p=0.0001) and the vasomotor GCS score (p=0.003), but did not report actual results. Limitations to this trial include the open-label design, small sample size, 30% dropout rate, short duration, and that vasomotor symptom changes were a secondary outcome. The authors failed to report any adverse effects associated with duloxetine use in this trial. Given the limitations of the data, duloxetine use should be limited until additional trials have been completed assessing its efficacy in hot flash relief as a primary outcome.

Selective Serotonin Reuptake Inhibitors

Paroxetine, sertraline, citalopram, escitalopram, fluvoxamine, and fluoxetine are antidepressants belonging to the SSRI class of drugs. The SSRIs work by inhibiting reuptake of serotonin, which should help to relieve hot flashes.[11] Over the last several years, increasing numbers of trials have assessed the use of each of these agents in the treatment of hot flashes; however, paroxetine remains the most studied of the SSRIs.[23,24,25,26,27]

Paroxetine Paroxetine was initially studied in breast cancer survivors for relief of hot flashes. Two small pilot studies (13 and 30 patients, respectively) in women taking paroxetine who had a history of breast cancer reported significant decreases in both hot flash frequency and severity.[23,24] A larger randomized controlled trial using paroxetine controlled release (CR) was conducted in 165 menopausal women having at least 14 bothersome hot flashes/week.[25] Only 12 patients (7.3%) had a history of breast cancer. Patients were randomly assigned to receive paroxetine CR 12.5 or 25 mg/day, or placebo for 6 weeks. The low-dose (12.5 mg/day) and high-dose (25 mg/day) groups both experienced reduced hot flash scores significantly more than placebo (62% and 65%, respectively, vs 37%, p<0.001). Strengths of this trial include that the patient population was predominantly healthy and without a history of breast cancer. Also, only 11 patients (6.7%) were taking either tamoxifen or raloxifene. One limitation is that the study population was predominantly Caucasian (87%). Also, this trial was of short duration.

A randomized, controlled, crossover study was conducted to assess the effectiveness of paroxetine 10 and 20 mg/day versus placebo in 151 menopausal women.[26] Eighty percent of participants were breast cancer survivors. Both the 10- and 20-mg doses significantly decreased the frequency of hot flashes and the hot flash scores compared with placebo. Based on these results relative to placebo, 10 and 20 mg/day similarly decreased the frequency of hot flashes (27% vs 25.2%) and the hot flash scores (31.9% vs 28.6%). The 10-mg dose seemed to be better tolerated since withdrawal rates associated with toxicity were greater in the 20-mg group compared with the 10-mg group (17% vs 5%, p=0.02). One significant limitation of this trial was 29% (44 patients) were not evaluable due to either incomplete or missing diaries. Other limitations were the short duration and limited generalizability of the results given 80% of patients were breast cancer survivors. In addition, more than 60% were receiving selective estrogen receptor modifiers and/or aromatase inhibitors.

Finally, a placebo-controlled trial was conducted in 56 menopausal women having at least 14 hot flashes/week that were of moderate-to-severe intensity (GCS vasomotor score > 3).[27] In patients receiving paroxetine CR 12.5 mg or placebo, the dosage could be titrated to 25 mg/day at week 2 based on the physician's impression of treatment response. At week 2 of the study, 63% of patients taking paroxetine and 82% of patients receiving placebo had the dosage increased to 25 mg/day. Median hot flashes/week decreased by 6.2 with paroxetine CR compared with 2.8 with placebo (p=0.03). The authors also reported significant changes in the GCS vasomotor subscores (p=0.04), but did not provide results. The results of this trial have more generalized application given the study population was relatively healthy menopausal women. In addition, most patients in this trial had undergone natural menopause. Two limitations of this trial include a primarily Caucasian study population and the short trial duration.

Paroxetine's ability to relieve hot flashes may be observed within 1-2 weeks of starting therapy.[25,26,27] Hot flash relief is similar with both low (10 and 12.5 mg) and high (20 and 25 mg) doses of paroxetine.[25,26] It would be best to start at 10 or 12.5 mg/day depending on the formulation and consider increasing to 20 or 25 mg/day if patients do not receive relief after 2 weeks since some patients may derive benefit from higher doses.[27] Adverse effects occurring more frequently with paroxetine for hot flashes than with placebo included headache, nausea, somnolence, insomnia, and dry mouth.[23,24,25]

One significant drug interaction occurred with tamoxifen that should be considered before starting paroxetine. Paroxetine has been shown to decrease the plasma concentrations of an active metabolite of tamoxifen.[28] Caution should be used when considering paroxetine in patients with a history of breast cancer who are taking tamoxifen. When possible, other SSRIs should be used until the clinical effects of this interaction are better understood.

Fluoxetine Fluoxetine's efficacy for relieving hot flashes was also first evaluated in women with a history of breast cancer.[8] This randomized, controlled, crossover study in 81 menopausal women reported that fluoxetine 20 mg/day resulted in significant reductions in hot flash frequency (19%, p=0.01) and scores (24%, p=0.02) compared with placebo. Three additional studies have since been conducted. An open-label study was conducted in 12 breast cancer survivors using fluoxetine 10 mg/day for 4 weeks. Compared with baseline, hot flash scores (46%, p=0.0006) and mean number of hot flashes/day (36.3%, p=0.001) decreased.[29] Limitations of this trial include its observational study design, small sample size, short duration, and limited generalizability (breast cancer survivors with 66% taking tamoxifen).

A 6-month, randomized, controlled trial assessed the efficacy of fluoxetine 20 mg/day compared with black cohosh 40 mg/day in 120 healthy menopausal women.[30] This study reported significant decreases in MKI scores for both groups compared with baseline at 3 months (p=0.001). However, the black cohosh group had significantly better MKI scores than those of the fluoxetine group at 3 months (13.9 ± 19.1 vs 18.5 ± 5.9, p=0.002). The 6-month MKI scores were not reported. At 6 months, however, black cohosh was significantly better than fluoxetine in reducing hot flash scores (85% vs 62%, p<0.001) and was better tolerated. This is one of the longest study durations assessing antidepressants in hot flash management. It is important to note, however, that the black cohosh product used in this study is not available in the United States, and reproducing these results would be difficult since there also are no standardized black cohosh products in the United States.

Finally, a randomized controlled trial was conducted over 9 months to compare citalopram 30 mg/day, fluoxetine 30 mg/day, or placebo in 150 relatively healthy, menopausal women.[31] All patients randomly assigned to the citalopram and fluoxetine groups had scheduled dosage titrations from the initial starting dose of 10 mg/day. The doses of both citalopram and fluoxetine at 1 month were increased to 20 mg/day, and at 6 months the doses were increased to 30 mg/day. All three groups had significant improvement in mean number of hot flashes and Kupperman Index (KI) scores from baseline (p<0.001). No significant differences were noted among the three groups in mean number of hot flashes or KI scores. In addition, there was no appreciable difference in symptom improvement with increasing the dose to 30 mg/day with both agents. A strength of this trial was its longer duration. It also included only women who had undergone natural menopause. A limitation of this study was that it did not have an inclusion criterion for minimum number or severity of hot flashes to be enrolled in this study. This could affect the response rate, as women with more frequent or severe hot flashes may have a greater response to therapy. In addition, this trial had a 36% dropout rate, which was similar among groups.

Fluoxetine's ability to relieve hot flashes may be observed within 3 weeks[8,29] of starting therapy and appears to peak by 6 months.[30] It is difficult to recommend the most appropriate dose for hot flash relief given the current data.[8,29,30,31] Since some patients may receive benefit from lower doses of fluoxetine, it may be best to start at 10 mg/day and increase to 20 mg/day if patients do not receive relief after 3 weeks. Fluoxetine's efficacy data are conflicting, and therefore fluoxetine should be considered second-line therapy among the SSRIs. Adverse effects that occurred more frequently with fluoxetine than with placebo or another active treatment in fluoxetine trials for hot flashes included nausea, appetite loss, sleep disturbances, dizziness, constipation, nervousness, mood changes, fatigue, unusual sweating, and dry mouth.[8,29,30,31] Dose did not significantly affect the frequency or severity of adverse effects reported.[31] Because fluoxetine and its active metabolite have a long half-life (4-16 days),[32] withdrawal symptoms after abruptly stopping fluoxetine are less than those seen with other SSRIs.[3]

Sertraline Three published studies have addressed the use of sertraline to treat hot flashes.[33,34,35] A 12-week, randomized, controlled, crossover study in 62 breast cancer survivors evaluated the effectiveness of sertraline 50 mg/day compared with placebo in hot flash management.[33] To be eligible for the study, women must have had a history of breast cancer, be taking tamoxifen, and have at least seven hot flashes/week. None of the women were free of hot flashes at the end of the first 6-week treatment period, which was the primary outcome. At week 12, the sertraline group had improved hot flash scores (−1.7 vs 3.4, p=0.03) and frequency (−0.9 vs 1.5, p=0.03) compared with placebo. This study's primary outcome (complete resolution of hot flashes) may have been unrealistic to accomplish. In addition, the authors did not appear to combine the results from each arm for each crossover phase for analysis. This trial was conducted exclusively in breast cancer survivors, all of whom were taking tamoxifen, which can limit its application. The minimum number of hot flashes for this study (at least 7/wk) was lower than that in other trials (at least 14/wk) that have shown benefit of SSRIs in hot flash relief.

The other two studies evaluated sertraline for hot flashes in relatively healthy, menopausal women.[34,35] A crossover study comparing sertraline 50 mg/day with placebo was conducted for 9 weeks in 97 women.[34] The mean weekly hot flash frequency (−5, placebo value not reported, p=0.002) and mean hot flash score (42 [−48%] vs 57 [−30%], p=0.001) was better with sertraline versus placebo. Of note, the women in this trial were experiencing a mean of 47.3 hot flashes/week that were of moderate severity, which is significantly greater than that reported in most studies. Even though this was quite high, none of these women were reported to be taking therapies that could increase hot flash frequency or severity. The authors did not report the percentage of patients who underwent surgical versus natural menopause. This trial population was predominantly Caucasian (80%), which limits generalized application. In addition, this trial was of short treatment duration.

A 6-week, randomized, controlled trial compared sertraline 100 mg/day with placebo in 99 relatively healthy, menopausal women.[35] To be eligible for the study, the women had to experience at least 14 hot flashes/week and have no history of breast cancer. No significant differences were noted in hot flash frequency (−38% vs −39%, p=0.94 ) or hot flash scores (−41% vs −42%, p=0.86) between the groups at 6 weeks, but both groups did experience improvements from baseline. This study population was more diverse (56% Caucasian) and relatively healthy. In addition, 99% had undergone natural menopause. This trial was limited by its short duration and small sample size.

Sertraline's ability to relieve hot flashes may be observed within 1-2 weeks of starting therapy and has been reported to peak as early as 3 weeks.[33,34,35] It is difficult to recommend the most appropriate dosage for hot flash relief given the current data. At least 50 mg/day is needed for efficacy of hot flash symptoms, and no benefit has been shown with dosages as high as 100 mg/day.[33,34,35] Given the inconsistent efficacy data, sertraline should be considered second-line therapy in the treatment of hot flashes among the SSRIs. Adverse effects occurring more frequently with sertraline than placebo included nausea, anxiety, fatigue, diarrhea, and dry mouth.[33,34,35]

Citalopram and Escitalopram Five studies have been published that assessed citalopram and escitalopram for hot flash symptoms.[31,36,37,38,39] Two were small pilot studies (18 and 22 patients, respectively) in primarily breast cancer survivors (83% and 90%, respectively). Both reported improvements in mean hot flash frequencies and hot flash scores compared with baseline.[36,37] The other three studies compared citalopram or escitalopram with active treatments.[31,38,39] A head-to-head comparison study with fluoxetine in healthy postmenopausal women was discussed previously.[31]

An 8-week, randomized, controlled trial was conducted in relatively healthy, menopausal women experiencing at least seven hot flashes/week.[38] This trial had four arms: citalopram, placebo, citalopram plus hormone therapy, and placebo plus hormone therapy. The citalopram dosage was started at 10 mg/day for 1 week, then increased to 20 mg/day for 3 weeks. The dosage could be increased to 40 mg/day for the next 4 weeks for patients in whom sufficient improvement was not observed. Patients in the hormone therapy arms received either conjugated estrogens 0.625 mg/day with or without medroxyprogesterone acetate 5 mg/day, or 17-β-ethinyl estradiol 2 mg/day plus norethindrone 1 mg/day. Progesterone was withheld in women who had undergone hysterectomy. The mean hot flash scores decreased significantly in all groups compared with baseline (citalopram −37%, placebo −13%, citalopram + hormone therapy −50%, placebo + hormone therapy −14%, p<0.01 for all comparisons). Also, the citalopram and citalopram plus hormone therapy arms were significantly better than the placebo or placebo plus hormone therapy arms in reducing hot flash scores (p<0.01). Also, the MKI scores significantly improved from baseline in all four groups; however, the citalopram and citalopram plus hormone therapy arms were significantly better than the placebo or placebo plus hormone therapy arm (p=0.001). Seventeen (10 in the citalopram arm and seven in the citalopram + hormone therapy arm) of 50 patients taking citalopram required a dose increase to 40 mg/day, which improved symptoms in 15 of those patients. Since this trial was conducted in healthy, primarily naturally (77%) menopausal women, the results apply to a broader audience. The trial required fewer weekly hot flashes for enrollment, yet demonstrated significant differences in MKI scores and hot flash scores. A limitation of this trial was its short duration.

Escitalopram 10 mg/day was evaluated in 32 patients in an 8-week, open-label study against ethinyl estradiol 5 μg/day and norethindrone 1 mg/day.[39] The patients had a diagnosis of depression and were menopausal, and the primary outcome was depression improvement measured by changes in MADRS scores. Improvements in menopausal symptoms were measured by changes in GCS scores. A significant difference was noted in the median decrease in overall GCS score (17.8 vs 8.75, p=0.01) in favor of escitalopram. The changes in the vasomotor subscores were similar between escitalopram and estrogen or norethindrone therapy. Limitations of this trial include a small sample size and short study duration. In addition, the primary outcome of this trial was an improvement in MADRS scores rather than improvement of vasomotor symptoms.

Study results for citalopram are inconsistent,[31,36,37,38] and there has been only one small study[39] with escitalopram. Given the limited and inconsistent data, it would be prudent to consider citalopram and escitalopram as second-line therapies among the SSRIs. Citalopram has been shown to be beneficial in patients who have failed venlafaxine therapy and should be considered in the event first-line therapies fail or are not tolerated.[37] If citalopram is to be used, the dosage should be started at 10 mg/day and titrated weekly to an effective dose (maximum 20-40 mg/day). Results can be seen as early as 1-2 weeks and peak effects seen as early as 4-8 weeks. Frequent adverse effects, based on clinical trials, include nausea, somnolence, increased perspiration, palpitations, and dry mouth.[31,36,37,38]

Fluvoxamine Two small studies (22 and 42 patients, respectively) assessed the efficacy of fluvoxamine in menopausal women.[40,41] A 6-week pilot study evaluated fluvoxamine 50 mg/day.[40] The authors reported significant improvement from baseline in vasomotor symptoms but did not report actual data regarding these changes. A randomized controlled trial assessed conjugated equine estrogen 0.3125 mg/day versus conjugated equine estrogen 0.3125 mg/day plus fluvoxamine 50 mg/day for 8 weeks in 42 oopherectomized women.[41] To be eligible for inclusion, the women had to have both depression and anxiety and be experiencing troublesome hot flashes. The primary outcome was improvement in depression. Both groups' daily hot flashes declined from baseline. However, at 8 weeks, the combination arm was significantly better than the monotherapy arm in mean number of daily hot flashes (0.9 vs 1.8, p=0.036). This study is limited by its small sample size, study population, and short duration. Another limitation is that hot flash assessment was not the primary outcome. More studies are needed that will assess fluvoxamine in the treatment of hot flashes before it should be used, given the small sample size in each study and that hot flash symptom reduction was a secondary outcome for both studies.

Other Antidepressants

Mirtazapine Mirtazapine is an antidepressant that has potent inhibitory effects on serotonin, histamine, and α2-receptors.[4] The inhibitory effects on both serotonin and α2-receptors are believed to be beneficial in helping with hot flash relief. A case series was the first report that mirtazapine might provide relief of hot flashes.[42] A 4-week, open-label pilot trial evaluated 22 women experiencing at least 14 hot flashes/week.[4] Fifty-nine percent of the women had a history of breast cancer. The dosage of mirtazapine started at 7.5 mg/night for 1 week, then increased to 15 mg/night for 1 week, then 30 mg/night for 1 week. At week 4, the patient could elect to continue with 30 mg/night or to decrease the dose to 15 mg/night. Ten patients opted to reduce the dose back to 15 mg at week 4. The median daily number of hot flashes and median hot flash score decreased by 52.9% and 59.5%, respectively, compared with baseline. The authors did not report results based on the final dose. This trial was limited by its open-label design, short study duration, and small sample size.

A 12-week, open-label pilot trial assessed mirtazapine 30 mg/day for hot flash relief.[43] The investigators evaluated 27 breast cancer survivors who were experiencing at least seven hot flashes/week. The hot flash frequency and score decreased significantly from baseline at week 4 (46.9% and 49%, p<0.05) and at week 8 (56.5% and 62.2%, p<0.05). These results were maintained through week 12. This trial is limited by its open-label design, small sample size, and rather short duration. Since the data with mirtazapine are limited to two small, open-label trials, it should be considered last-line therapy.

In addition to lack of efficacy, mirtazapine may be limited by its associated adverse effects. The adverse effects that occurred more frequently compared with baseline included increased appetite, somnolence, dry mouth, weight gain, and dizziness.[4,43] Also, the adverse effects occurred more frequently on initiation of therapy but subsided with time.[43] Although these reported adverse effects are similar to those reported in the SSRI and SNRI studies, it should be noted that somnolence, appetite stimulation, and weight gain typically occur more frequently and severely with mirtazapine than with SSRIs and SNRIs.

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