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Vasomotor symptoms, including hot flushes and night sweats, are among the most commonly reported symptoms during the menopausal transition. Prevalence rates vary worldwide,1,2 but the National Institutes of Health State-of-the-Science Conference Statement reported U.S. rates of 35–50% in perimenopausal women and 30–80% in postmenopausal women.3 Vasomotor symptoms and associated sleep disruptions have a negative impact on health-related quality of life,4 and women who experience menopausal hot flushes are more likely to seek medical care than those who do not.5
Currently, hormone therapy (HT)—estrogen with or without progesterone or a synthetic progestin—remains the first-line treatment for vasomotor symptoms.2 Estrogen, with or without progesterone, consistently reduces the number and severity of menopausal hot flushes compared with placebo.6 Many women, however, either cannot or choose not to use HT. Although there are currently no alternatives to HT approved by the U.S. Food and Drug Administration (FDA) for treatment of vasomotor symptoms, a number of centrally acting compounds have been assessed in placebo-controlled trials.7 Several selective serotonin reuptake inhibitors (SSRIs)8–15 and a serotonin norepinephrine reuptake inhibitor (SNRI)16–20 are among those centrally acting compounds that have shown some efficacy in relieving hot flushes, although studies were small and of short duration and in several the study populations were not restricted to healthy postmenopausal women. There is a paucity of large, randomized, placebo-controlled trials evaluating centrally acting alternatives to HT in menopausal women with moderate-to-severe hot flushes.
Desvenlafaxine succinate (desvenlafaxine), the succinate salt form of the major active metabolite of venlafaxine, is a novel SNRI with therapeutic potential for the treatment of moderate-to-severe vasomotor symptoms associated with menopause.21 As neurotransmitters in the thermoregulatory nuclei of the hypothalamus, serotonin and norepinephrine are thought to play an important role in normal thermoregulatory function and in the dysfunction that results in vasomotor symptoms,22 a hypothesis further supported by the reductions in hot flushes reported in SSRI/SNRI vasomotor symptoms trials.10,13,15,18
Research has indicated that SSRIs and SNRIs each have unique functional ratios of selectivity for serotonin and norepinephrine transporters,23,24 but the optimal activity ratio for restoration of “normal” function has not been determined for any specific disease indication. Desvenlafaxine is highly selective for serotonin and norepinephrine transporters, with weak affinity for other receptors and transporters.25 In rats, desvenlafaxine rapidly enters the hypothalamus, selectively increases serotonin and norepinephrine levels at that site,26 and restored thermoregulatory function in two separate models of vasomotor symptoms in ovariectomized rats.21 Preclinical in vitro and in vivo studies show that it is well absorbed with good bioavailability, and in studies in healthy volunteers, it was well tolerated with few serious adverse events reported. It shows minimal inhibition of the major enzymes in the cytochrome P450 family, a principal site of drug-drug interactions (Shilling, manuscript in preparation). The objective of this study was to estimate the safety, tolerability, and efficacy of four doses of desvenlafaxine (50, 100, 150, and 200 mg/d) compared with placebo for the treatment of hot flushes associated with menopause. It was planned as a dose-ranging study and designed according to FDA guidelines and European Medicines Agency Committee for Medicinal Products for Human Use guidance for vasomotor symptoms trials.27,28
MATERIALS AND METHODS
This multi-center, randomized, double-blind, placebo-controlled trial was conducted at 37 U.S. sites, including private or institutional practice and research centers. Healthy postmenopausal women (body mass index 40 kg/m2 or less) who experienced at least seven self-reported moderate-to-severe hot flushes per day (or 50 or more per week) were eligible.27 Menopause was defined as spontaneous amenorrhea of at least 12 months, spontaneous amenorrhea of at least 6 months with serum follicle-stimulating hormone levels greater than 40 milli-International Units/mL, or bilateral oophorectomy performed at least 6 weeks before screening, with no age restrictions.
Women with known hypersensitivity to venlafaxine were not eligible for the trial. Women were excluded if they had used estrogen-, progestin-, androgen-, or selective estrogen receptor modulator–containing drug products within a period of time before screening depending on route of administration (oral, transdermal, or intrauterine within 8 weeks; vaginal within 4 weeks; progestin implants or estrogen injectables within 3 months; or estrogen pellets or progestin injectables within 6 months) in accordance with FDA guidelines.27 Women who used medications to relieve vasomotor symptoms or psychoactive medications within 4 weeks before screening, or any investigational drug within 30 days before screening were also excluded. Women were not eligible if they had a history of seizure disorder; myocardial infarction (within 6 months); malignancy other than basal or squamous cell carcinoma (within 2 years); glaucoma or raised intraocular pressure; or hepatic, renal, or other medical disease. Women also were ineligible if they had current major depressive, bipolar, psychotic, or generalized anxiety disorder requiring therapy; untreated malabsorption disorder; persistent elevated blood pressure; or other clinically important abnormalities at screening.
The protocol and amendment received approval from the institutional review board at each site. There were no systematic deviations from protocol. The study was conducted according to the Declaration of Helsinki. Written informed consent was obtained from participants before their enrollment. Participants were given a number code for identification, and all participant information and identities were kept confidential.
Women were randomized to receive one of four doses of desvenlafaxine (50, 100, 150, or 200 mg/d) or placebo for 52 weeks. A 2:2:2:2:1 allocation was used to increase the number of desvenlafaxine participants with long-term safety data to comply with International Conference on Harmonisation guidelines without overpowering the study. Participants were allocated to treatment groups using a computerized randomization/enrollment system into which study site personnel entered information and from which subject randomization numbers were issued. Participants and all study site and Wyeth personnel were blinded to treatment allocation. Desvenlafaxine and matched placebo tablets were shipped to study sites by Wyeth Research in individual packages code-labeled with randomization numbers. All participants were instructed to take tablets orally with food at approximately the same time each day and to return empty packs and unused tablets to the investigator. Treatment compliance (defined as taking 80% of assigned tablets) was determined by returned pill counts. Primary efficacy evaluations were completed at 4 and 12 weeks. Safety and tolerability data were collected for 52 weeks, with a follow-up evaluation approximately 15 days after the last day of treatment. There was no dose titration at initiation of therapy or tapering at cessation of treatment.
Women maintained daily diaries throughout the trial for recording the frequency and severity of hot flushes. Participants categorized hot flush severity as mild (fleeting warm sensation, no perspiration, does not disrupt activity), moderate (warm sensation with sweating, does not disrupt activity), or severe (hot sensation with sweating, disrupts activity). For the initial 12 weeks of treatment, each woman also kept a daily record of the number of nighttime awakenings due to hot flushes. The primary end points of the study were change from baseline in daily number of moderate-to-severe hot flushes and change from baseline in average daily severity score compared with placebo at weeks 4 and 12. Secondary end points included the proportion of women achieving a 50% and 75% reduction from baseline in number of hot flushes (50% responder rates reported elsewhere), the time to onset of action (50% reduction in number of hot flushes for 3 consecutive days), the change from baseline in daily number of mild, moderate, and severe hot flushes, and the change from baseline in daily number of nighttime awakenings due to hot flushes at weeks 4 and 12.
At baseline and weeks 4, 12, and 52, participants completed five self-administered questionnaires: the Profile of Mood States, the Work Limitations Questionnaire, the Menopause Symptoms Treatment Satisfaction Questionnaire, the Sexual Functioning Questionnaire, and the EuroQuality of Life Visual Analog Scale. Results from these secondary outcomes will be reported in separate publications. Safety was assessed through scheduled physical examinations, vital sign measurements, clinical laboratory testing, and electrocardiograms. Clinical laboratory testing included hematology, fasting blood chemistry, and urine assessment. Adverse event and concomitant medication data were collected at each visit throughout the study.
Statistical analysis was carried out by the Biostatistics Section of Wyeth Research. Target enrollment was 120 for each desvenlafaxine group and 60 for the placebo group to ensure a sample size of 100 in each desvenlafaxine dose group and 50 in the placebo group. These sample sizes provided greater than 90% power to detect a difference in mean hot flush score of 2 (assuming a standard deviation of 3.5) and a difference in mean severity score of 0.6 (assuming an standard deviation of 0.9) between a desvenlafaxine group and the placebo group using a two-group t test with a 0.024 two-sided significance level, adjusted for interim analysis and multiple comparisons. When the target number was reached, those subjects who had already signed an informed consent and were involved in the screening were allowed to remain in the study, and thus the final enrollment exceeded the target.
Efficacy analyses were carried out on the intent-to-treat population (women who were randomly assigned to a treatment group, received at least one dose of test article, recorded 5 or more days of data for the baseline week, and had data for 5 or more days during at least 1 week in the first 12 on-therapy weeks after the baseline week). Missing data were dealt with using a last-observation-carried-forward approach. Safety and tolerability analyses included all women who were randomly assigned to a treatment group and received at least one dose of test article.
The average daily number of moderate-to-severe hot flushes, average daily severity score, and average daily number of nighttime awakenings due to hot flushes were calculated for each week based on the days with available data at each time point. The average daily hot flush severity score was calculated as follows: ([number of mild hot flushes×1]+[number of moderate hot flushes×2]+[number of severe hot flushes×3])/total number of hot flushes on that day. For efficacy variables, the change from baseline for the desvenlafaxine and placebo groups was compared using analysis of covariance (ANCOVA) with treatment and study site as factors and baseline value as covariate. Pairwise comparisons between the desvenlafaxine groups and the placebo group were made using t tests based on the least-squares means and pooled error terms obtained from the ANCOVA. An interim analysis was performed when half of subjects enrolled had 4 weeks of therapy to select doses for future studies.
Planned comparisons between desvenlafaxine dose groups and placebo were made for primary and secondary end points at weeks 4 and 12. The P value used for the planned comparisons was .048, adjusting for an interim analysis of number of hot flushes at week 4 at P=.005.29 To control for type I error from multiple comparisons between desvenlafaxine doses and placebo, comparisons were done in a stepwise manner. The trial was designed as a dose-ranging study, and thus the two highest-dosed groups were assessed first using a .024 significance level (statistical penalty for interim analysis at week 4), with subsequent tests at the .048 significance level for the lower doses if either of the higher doses reached significance.30 The stepwise procedure was used for primary efficacy end points only.
Differences between groups in baseline symptoms and demographic characteristics were assessed using one-way analysis of variance or χ2 tests. The proportion of participants with a 75% or greater reduction in number of hot flushes was analyzed by logistic regression, with treatment and study site as covariates. The time to onset of action was calculated as the median number of days to the first of 3 or more consecutive days of at least 50% from baseline in the daily number of moderate and severe hot flushes.
For clinical laboratory tests, ANCOVA was used for comparisons among treatment groups, with baseline value as the covariate. Categorical data, including incidence rates for all treatment-emergent adverse events, discontinuation symptoms (adverse events that were not present during the last 7 days of the treatment period and began during the 15-day posttherapy period or events that became more severe during the posttherapy period), and discontinuations from the study, were compared using the Fisher exact test.
Between December 2003 and May 2005, 1,169 women were screened, and 707 were randomly assigned to receive placebo or 50, 100, 150, or 200 mg/d of desvenlafaxine (Fig. 1). Of these, 620 of 707 women (87.7%) completed at least one on-therapy evaluation for primary efficacy end points, 519 of 620 women (83.7%) completed 12 weeks of treatment, and 368 of 620 women (59.4%) completed 50 weeks or more. Mean therapy duration was 235 days, with 230 days for desvenlafaxine-treated women and 272 days for placebo-treated women. Desvenlafaxine groups had significantly more discontinuations than placebo (Fig. 1; P = .04). During the first week on therapy, treatment compliance was 91%, 92%, 82%, 73%, and 99%, respectively, for the desvenlafaxine 50-, 100-, 150-, and 200-mg groups and placebo. All other weeks, compliance was approximately 90% for all groups, with no differences between groups.
Participant demographics and baseline values for hot flush frequency and severity and nighttime awakenings for the intent-to-treat population are summarized in Table 1. There were no statistically significant differences between treatment groups in demographic characteristics or baseline efficacy measures. In all groups, the majority of women were white (85.2%) and had natural menopause with an intact uterus (78.2%). Participants' mean age was 53.47 years (range 37–78), and the mean number of years since menopause was 4.7 years (range 0.5–23.7) for natural menopause and 10.7 years (range 0.2–44.1) for surgical menopause. The mean and standard deviation of age and years since natural menopause were numerically higher for the placebo group than the desvenlafaxine groups, likely due to the smaller group size, but those differences were not statistically significant. At baseline, the mean daily number of moderate-to-severe hot flushes was 10.9 and the mean number of nighttime awakenings was 3.7.
The decrease from baseline in the average daily number of moderate-to-severe hot flushes over 12 weeks is shown for each group in Figure 2. Reductions from baseline to week 12 were 55%, 64%, 60%, and 60% for the desvenlafaxine 50-, 100-, 150-, and 200-mg groups, respectively, and 51% for the placebo group.
Treatment with desvenlafaxine 100 mg/d produced a significantly greater decrease from baseline in the average daily number of moderate-to-severe hot flushes compared with placebo at both weeks 4 (–6.62 compared with –5.22 hot flushes; P=.013) and 12 (–7.23 compared with –5.50 hot flushes; P=.005). The reductions in the number of moderate-to-severe hot flushes for all other desvenlafaxine dose groups were smaller than that produced by the 100-mg dose. The desvenlafaxine 150-mg group differed significantly from the placebo group at the 0.024 level at week 12 (–6.94 hot flushes; P=.020) but not at week 4. There was no significant difference from placebo for the desvenlafaxine 50- and 200-mg doses at either time point (Table 2). The decrease in the average daily number of mild, moderate, and severe hot flushes was significantly greater for desvenlafaxine 100- and 150-mg groups compared with placebo at weeks 4 (P=.004 and P=.006, respectively) and 12 (Table 2; P=.016 and P=.020, respectively); the desvenlafaxine 200-mg group differed significantly from the placebo group at week 4 only (P=.016).
The desvenlafaxine 100-mg (31% reduction; P=.002) and 200-mg (27% reduction; P=.013) groups had a significantly greater decrease from baseline in average daily severity scores compared with placebo (18% reduction) at week 12, but not at week 4. The desvenlafaxine 50- and 150-mg groups did not differ from the placebo group at either time point.
Figure 3 shows the proportion of women with a 75% or greater decrease from baseline in average daily number of hot flushes at weeks 4 and 12. A significantly greater percentage of women in the desvenlafaxine 100-, 150-, and 200-mg groups had achieved a 75% or greater reduction compared with the placebo group at week 4 (P=.005, P=.003, and P=.021, respectively). At week 12, the desvenlafaxine 100- and 200-mg groups had significantly more 75% responders than the placebo group (P=.003 and P=.022, respectively). The numbers needed to treat for benefit based on the 75% responder rates were 4.7 (95% confidence interval [CI] 3.0–13.2) and 6.1 (95% CI 3.4–39.8) for the desvenlafaxine 100- and 200-mg groups, respectively. The median time to onset of efficacy, defined as the time to reach a 50% reduction from baseline in hot flushes for at least 3 consecutive days, was significantly shorter for all desvenlafaxine groups (within 1 week) compared with placebo (3–4 weeks; Table 2).
Treatment with desvenlafaxine 100, 150, and 200 mg significantly reduced the average daily number of nighttime awakenings due to hot flushes compared with placebo. At week 12, the number of nighttime awakenings had decreased by an average of 2.77 per night in the desvenlafaxine 100-mg group (P=.013), 2.69 in the 150-mg group (P=.034), and 2.68 in the 200-mg group (P=.043), all significantly different from the placebo group (2.21 fewer awakenings). The desvenlafaxine 50-mg group did not differ significantly from the placebo group in the number of nighttime awakenings reported at week 12 (–2.30).
Six hundred eighty-nine participants took at least one dose of desvenlafaxine or placebo and were included in safety evaluations. The percentage of women in the placebo group reporting treatment-emergent adverse events was 87%. Treatment-emergent adverse events were reported by 90% of women in the desvenlafaxine 50-mg group, 94% in the 100-mg group, 95% in the 150-mg group, and 97% in the 200-mg group. Women in the desvenlafaxine 150- and 200-mg groups reported significantly more treatment-emergent adverse events (P=.040 and P=.006, respectively) than women in the placebo group; those in the 50- and 100-mg dose groups did not. Desvenlafaxine-treated women reported significantly more treatment-emergent adverse events than placebo controls during the first week of therapy only. There were no differences between groups in the incidence of newly emergent adverse events after the first week.
Discontinuations due to adverse events occurred at significantly higher rates in the desvenlafaxine 150- and 200-mg groups compared with placebo (both comparisons, P<.001); the desvenlafaxine 50- and 100-mg groups did not differ from placebo (Fig. 1). Overall, the incidence of discontinuations due to adverse events was significantly higher in desvenlafaxine groups compared with placebo (P<.001) during the first week on-therapy only, with no significant differences between groups after week 1.
The most common adverse drug reactions (noxious and unintended responses to treatment that are at least possibly causally related to the treatment) associated with desvenlafaxine during the trial are listed in Table 3. Adverse drug reactions with an incidence of 10% or more of desvenlafaxine-treated women included asthenia, constipation, dry mouth, nausea, dizziness, insomnia, and somnolence. A dose-related trend was seen for chills, hypertension, anorexia, constipation, dry mouth, nausea, vomiting, dizziness, insomnia, decreased libido, and abnormal thinking. The desvenlafaxine 50-mg dose group reported significantly less asthenia, nausea, and somnolence than all higher desvenlafaxine dose groups.
Nausea was the most common adverse drug reaction associated with desvenlafaxine treatment. Nausea was mild or moderate in severity in most cases and resulted in more discontinuations compared with placebo only during the first week of treatment. The incidence of nausea was dose-dependent. During the first week, there was a significantly lower incidence of nausea in the 50-mg group (18%) compared with the higher doses (33%, 39%, and 42% for the desvenlafaxine 100-, 150-, and 200-mg groups, respectively). The mean duration of nausea episodes was 14–17 days for desvenlafaxine-treated women, with a median of 3 days, and 12 days for the placebo group, with a median of 2.5 days.
Discontinuation symptoms were reported at termination of therapy by 24 women (31%) in the placebo group and 291 women (48%) in the desvenlafaxine-treatment groups. Dizziness, nausea, and headache were the most commonly reported discontinuation symptoms. Overall, discontinuation symptoms did not increase with increasing desvenlafaxine dose. However, longer therapy duration (greater than 12 weeks) was associated with a higher incidence of discontinuation symptoms for all groups.
Twenty-seven desvenlafaxine-treated women reported serious adverse events during the on-therapy or posttherapy period. Three participants had serious adverse events that were considered possibly related to desvenlafaxine: two women with increased liver function test values and one woman with cholecystitis. Five desvenlafaxine-treated women reported three primary events of coronary occlusion with revascularization and two primary events of myocardial infarction. Each of the five women had three or more cardiovascular risk factors at baseline, including family history, personal history of angina, smoking, hypertension, high body weight, and hyperlipidemia. In all cases, cardiac catheterization revealed evidence of extensive occlusion, suggestive of long-standing coronary atherosclerosis. Cardiovascular events were distributed across all dose groups. No cardiovascular events were reported in the placebo group, but the placebo group included 77 participants, and only 66 of them had data beyond 3 months. Due to multiple underlying cardiac risk factors in the women who experienced these events and because the cardiovascular events were rare, no dose or causal relationship could be ascertained.
More participants in desvenlafaxine groups reported hypertension as an adverse event compared with placebo, but no dose group had a significantly greater incidence than the placebo group. Hypertension was reported in 5.9% of desvenlafaxine-treated women and 1.3% of placebo-treated women, with the highest incidence reported in the desvenlafaxine 200-mg dose group (7.9%). There was no significant difference among groups in reports of decreased libido, abnormal orgasm, anorgasmia, or abnormal sexual function.
Desvenlafaxine 100 mg/d significantly reduced the number and severity of hot flushes in postmenopausal women compared with placebo in this randomized, double-blind trial. Evidence of efficacy was demonstrated as rapidly as within 1 week of treatment. The placebo effect on the frequency of hot flushes, a 51% reduction from baseline at week 12, was high, but similar high placebo effects have been reported in vasomotor symptoms trials.6,31 Nonetheless, desvenlafaxine 100 mg did separate from placebo on the primary efficacy end points, with a 64% reduction from baseline in number of moderate-to-severe hot flushes at week 12. Half of all women receiving the desvenlafaxine 100-mg dose achieved a 75% reduction in the number of moderate-to-severe hot flushes compared with 29% of the placebo group. Efficacy, as measured by time to reach a 50% reduction from baseline in number of hot flushes, was reached within 1 week of treatment, compared with 3–4 weeks for placebo. Desvenlafaxine treatment also significantly reduced nighttime awakenings due to hot flushes.
Based on a 1-year course of therapy, desvenlafaxine was generally well tolerated at all doses tested. The most common drug reactions were nausea, dizziness, and insomnia, similar in type and frequency to those that would be expected with other SSRIs or SNRIs.32,33 There was no significant difference between desvenlafaxine treatment groups and placebo in reports of decreased libido. Most adverse events occurred early in therapy and were mild or moderate, but led to discontinuation in more desvenlafaxine-treated women compared with placebo. In this study, the assigned dose of desvenlafaxine was administered on the first day of therapy with no titration and discontinued abruptly at the end of the study with no tapering period. Experience with other SSRIs/SNRIs shows that dose titration improves the early tolerability of this class of drugs.,33,34 The desvenlafaxine 50-mg group reported significantly fewer adverse events and had 2–3 times fewer discontinuations due to adverse events compared with higher-dose desvenlafaxine groups during the first week of therapy, suggesting that women may benefit from the use of a 50-mg dose when initiating treatment with desvenlafaxine. The incidence of adverse events occurring after abrupt discontinuation of desvenlafaxine, particularly among women treated longer than 12 weeks (compared with less than 12 weeks of therapy), suggests that gradual reduction of desvenlafaxine may be beneficial to patients. Similar recommendations are not uncommon for SSRIs and SNRIs, particularly those with a relatively short half-life, such as desvenlafaxine.35,36
Although there has been no major concern with ischemic cardiovascular events in the SNRI class of drugs, treatment-emergent hypertension has been reported with high doses of venlafaxine.34,37 Monitoring blood pressure at initiation and during treatment with desvenlafaxine is recommended. The few cardiovascular events reported in this trial resulted in an incidence of 0.8% in the desvenlafaxine safety population. At this rate, a comparable occurrence of less than one (0.6) cardiovascular event would be expected among the 77 placebo-treated women. The relationship of cardiovascular events to desvenlafaxine could not be determined because the events were rare and there was no dose clustering. The incidence rate in the placebo group was zero, consistent with all incidence rates being less than 1%. The participant distribution among treatment groups was not powered to establish whether the number of cardiovascular events was statistically significant. No cardiovascular events occurred in three additional clinical trials of desvenlafaxine for vasomotor symptoms (n=1,469; Archer DF, DuPont CM, et al manuscript in preparation; Bouchard P et al manuscript in preparation; Archer DF, Seidman L, et al manuscript in preparation). When all four ongoing programs for desvenlafaxine indications (vasomotor symptoms, major depressive disorder, fibromyalgia, and diabetic peripheral neuropathy) are considered, including over 6,000 participants exposed to desvenlafaxine for durations up to 1 year, an increased risk of cardiovascular events with desvenlafaxine has not been noted.
Conclusions drawn from the results of this study are limited by a lack of diversity in the subject population. Because over 80% of the women were white, it is not clear how well the results will generalize to nonwhite patients. Safety and tolerability conclusions are limited by the small size of the placebo group and by the absence of titration and tapering protocols, which likely reduced tolerability at onset and discontinuation of therapy.
Hormone therapy is the most effective treatment for vasomotor symptoms,3 reducing the number of hot flushes by approximately 75% in a meta-analysis of vasomotor symptoms trials.6 There is an unmet need for an effective nonhormonal treatment, however, and desvenlafaxine efficacy compares favorably with other centrally acting, nonhormonal drugs.7 Desvenlafaxine was generally well tolerated, based on 1-year therapy duration. These results suggest that desvenlafaxine 100 mg/d may provide an effective nonhormonal therapy for moderate-to-severe vasomotor symptoms associated with menopause. Additional studies to confirm the efficacy and safety of the 100-mg dose and to determine whether dose titration and tapering strategies can improve tolerability and reduce discontinuations due to adverse events such as nausea are ongoing.
1. Avis NE, Brockwell S, Colvin A. A universal menopausal syndrome? Am J Med 2005;118:37–46.
2. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause 2004;11:11–33.
3. National Institutes of Health. National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann Intern Med 2005;142:1003–13.
4. Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes 2005;3:47–56.
5. Guthrie JR, Dennerstein L, Taffe JR, Donnelly V. Health care-seeking for menopausal problems. Climacteric 2003;6:112–7.
6. Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004;(4):CD002978.
7. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057–71.
8. Barton DL, Loprinzi CL, Novotny P, Shanafelt T, Sloan J, Wahner-Roedler D, et al. Pilot evaluation of citalopram for the relief of hot flashes. J Support Oncol 2003;1:47–51.
9. Loprinzi CL, Flynn PJ, Carpenter LA, Atherton P, Barton DL, Shanafelt TD, et al. Pilot evaluation of citalopram for the treatment of hot flashes in women with inadequate benefit from venlafaxine. J Palliat Med 2005;8:924–30.
10. 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.
11. Stearns V, Isaacs C, Rowland J, Crawford J, Ellis MJ, Kramer R, et al. A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann Oncol 2000;11:17–22.
12. Weitzner MA, Moncello J, Jacobsen PB, Minton S. A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer. J Pain Symptom Manage 2002;23:337–45.
13. 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.
14. Loprinzi CL, Barton DL, Carpenter LA, Sloan JA, Novotny PJ, Gettman MT, et al. Pilot evaluation of paroxetine for treating hot flashes in men. Mayo Clin Proc 2004;79:1247–51.
15. 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.
16. Loprinzi CL, Pisansky TM, Fonseca R, Sloan JA, Zahasky KM, Quella SK, et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998;16:2377–81.
17. Quella SK, Loprinzi CL, Sloan J, Novotny P, Perez EA, Burch PA, et al. Pilot evaluation of venlafaxine for the treatment of hot flashes in men undergoing androgen ablation therapy for prostate cancer. J Urol 1999;162:98–102.
18. 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.
19. Barton D, La VB, Loprinzi C, Novotny P, Wilwerding MB, Sloan J. Venlafaxine for the control of hot flashes: results of a longitudinal continuation study. Oncol Nurs Forum 2002;29:33–40.
20. Biglia N, Torta R, Roagna R, Maggiorotto F, Cacciari F, Ponzone R, et al. Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors. Maturitas 2005;52:78–85.
21. Deecher DC, Alfinito PD, Leventhal L, Cosmi S, Johnston GH, Merchenthaler I, et al. Alleviation of thermoregulatory dysfunction with the new serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized rodent models. Endocrinology 2007;148:1376–83.
22. Deecher DC. Physiology of thermoregulatory dysfunction and current approaches to the treatment of vasomotor symptoms. Expert Opin Investig Drugs 2005;14:435–48.
23. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 1997;283:1305–22.
24. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology 2001;25:871–80.
25. Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, et al. Desvenlafaxine succinate: a new serotonin and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther 2006;318:657–65.
26. Alfinito PD, Huselton C, Chen X, Deecher DC. Pharmacokinetic and pharmacodynamic profiles of the novel serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized Sprague-Dawley rats. Brain Res 2006;1098:71–8.
27. U.S. Food and Drug Administration. Guidance for Industry. Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms - recommendations for clinical evaluation. Rockville (MD): U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER); 2003.
28. EMEA CHMP. Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. London: European Medicines Agency; 2005.
29. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549–56.
30. Bauer P. Multiple testing in clinical trials. Stat Med 1991;10:871–89.
31. 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.
32. Rudolph RL, Derivan AT. The safety and tolerability of venlafaxine hydrochloride: analysis of the clinical trials database. J Clin Psychopharmacol 1996;16:54S–9S.
33. Masand PS, Gupta S. Selective serotonin-reuptake inhibitors: an update. Harv Rev Psychiatry 1999;7:69–84.
34. Thase ME, Shelton RC, Khan A. Treatment with venlafaxine extended release after SSRI nonresponse or intolerance: a randomized comparison of standard- and higher-dosing strategies. J Clin Psychopharmacol 2006;26:250–8.
35. Haddad PM. Antidepressant discontinuation syndromes: clinical relevance, prevention and management. Drug Saf 2001;24:183–97.
36. Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Young AH, et al. Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Discontinuation Consensus Panel. J Clin Psychiatry 1997;58 suppl 7:5–10.
37. 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. Leon Speroff, Margery Gass, Ginger Constantine, Sophie Olivier, for the Study 315 Investigators
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