Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors

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1 Maturitas 52 (2005) Current opinion Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors N. Biglia a,, Riccardo Torta b, R. Roagna a, F. Maggiorotto a, F. Cacciari a, R. Ponzone a, F. Kubatzki a, P. Sismondi a a Academic Gynaecological Oncology Department, University of Turin, IRCC (Institute for Cancer Research and Treatment) of Candiolo, Turin and Mauriziano Umberto I Hospital, Largo Turati 62, Torino 10128, Italy b Department of NeuroScience, University of Turin, Turin, Italy Received 10 September 2004; received in revised form 3 January 2005; accepted 4 January 2005 Abstract Objective : To evaluate the efficacy and tolerability of long-term treatment with venlafaxine at low dose for the reduction of vasomotor symptoms in breast cancer survivors. Design : Forty consecutive breast cancer patients suffering troublesome hot flushes have been treated for 8 weeks with venlafaxine XR 37.5 mg/day in an open-label study. Vasomotor symptoms have been evaluated before starting treatment and every 4 weeks with a hot flushes diary pointing out the number and the severity of vasomotor symptoms. A Beck Depression Inventory (BDI) was completed at baseline and at the end of the treatment. Results : Thirty patients had completed the first 4 weeks of treatment, reporting a reduction of hot flushes frequency of 39% as compared to baseline (p < 0.001). After 8 weeks of treatment, a further significant reduction was observed both for the hot flushes frequency ( 53%; p < 0.001) and for the hot flushes score ( 59%; p < 0.001), a measure which reflects both the number and the severity of hot flushes. Very few side effects were reported, mostly nausea in the first 2 weeks of assumption and mouth dryness. Only 23 women had completed BDI at week 8; a reduction of 23% was observed (p = 0.000). Conclusion : Venlafaxine is an effective treatment for the relief of vasomotor symptoms in patients previously treated for breast cancer. A favourable effect is maintained also in those patients using tamoxifen as adjuvant therapy. The use of the low dose (37.5 mg/day) is associated with minimal side effects and produces a good improvement in hot flushes if pursued over 8 weeks Elsevier Ireland Ltd. All rights reserved. Keywords: Venlafaxine; Hot flushes; Breast cancer 1. Introduction Corresponding author. Tel.: ; fax: address: nbiglia@mauriziano.it (N. Biglia). Hot flushes are a frequent and severe symptom for many breast cancer patients [1,2]. Hot flushes may be more troublesome in women treated for breast can /$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved. doi: /j.maturitas

2 N. Biglia et al. / Maturitas 52 (2005) cer than in other menopausal women for several reasons including: (1) discontinuation of hormone therapy (HT) at the time of cancer diagnosis; (2) premature menopause due to chemotherapy; (3) side effects of antiestrogen, increasing the frequency and the severity of vasomotor symptoms [3]. Estrogen and progestogen supplementations are effective in reducing hot flushes [4], but physicians are reluctant to start hormone therapy because of fear of cancer recurrence [5,6]. Recently, the randomized study from Sweden Hormone Replacement Therapy after Breast Cancer Diagnosis Is It Safe? (HABITS) has been stopped because of an increased risk of breast cancer events in patients receiving HT as compared to no such therapy (RR 3.5; 95% CI ) [7]. A series of trials with non-hormonal agents have been conducted for the control of hot flushes, using clonidine [8,9], methyldopa [10], Vitamin E [11], belladonna alkaloids [12], phytoestrogens supplementations [13], but no single agent has proven its usefulness for long term treatment without substantial side effects. The physiology of hot flushes has not been fully elucidated. It is well known that estrogen and progestogen strongly interact with several neurotransmitters and this has led to a range of non-hormonal treatments that act via noradrenergic, serotoninergic or dopaminergic systems [14]. Recently, Slopien et al. [15] demonstrated that serum serotonin concentrations in postmenopausal women are related to the severity of climacteric symptoms: particularly, the mean serum serotonin concentration in a group of patients with mild climacteric symptoms was 97.7 ng/ml (S.D. ± 16.6 ng/ml) and in the group of patients with moderate and severe climacteric symptoms was 36.2 ng/ml (S.D. ± 24.1 ng/ml). The putative mechanism of Selective Serotonine Reuptake Inhibitors (SSRIs) on hot flushes is not only related to the 5HT plasma levels but it is certainly also related to the relationship between 5HT and estrogen at CNS level, and to the 5HT differentiated activity on vessels. Several randomized placebo-controlled trials showed that antidepressants acting on serotonin system, such as fluoxetine [16], paroxetine [17] and sertraline [18] could safely reduce hot flushes in breast cancer patients: paroxetine [19] and sertraline [20] have been also evaluated with this objective in small open-label studies showing a good efficacy. Also a specifical pharmacological activity on the 5HT(2A) receptor subtype may play a key role in the occurrence of hot flushes, as observed with mirtazapine, a Noradrenergic and Selective Serotoninergic Antidepressants (NaSSAs) [21,22]. Other serotoninergic antidepressants, such as trazodone, even though acting on serotoninergic system, can be particularly useful for those patients whose climacteric symptoms have a marked component of anxiety [23]. Recently, the attention has been focused on other antidepressant classes, such as SNRIs, compounds acting both on norepinephrine and serotonine (SNRIs) [24]; among all drugs, venlaflaxine is the most extensively investigated by open label [25] and randomized controlled studies [26]. Venlafaxine is a bicyclic phenylethylamine derivative with a structure and a chemical profile that distinguishes it from SSRIs and that is responsible for its pharmacological activity, related to the blockade of the reuptake of both serotonine and norepinephrine. Venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) have no substantial affinity for muscarinic, cholinergic, histaminic H1 or alfa-adrenergic receptors, with consequently lower autonomic side effects. Venlafaxine is available in immediate-release (IR) formulation: ODV half-life is about 10 h (and venlafaxine half-life = 4 h) so this drug can be given in two divided doses. An extended-release (XR) preparation is also available in 37.5, 75 and 150 mg doses: once-a-day XR dosing achieves bioavailability equivalent to that of twice-aday dosing with IR formulation. The XR preparation is also associated to a better compliance and demonstrates both antidepressant and, after 2 3 weeks of treatment, also a good anxiolitic effects. The largest placebo-controlled study, published by Loprinzi et al. [26], concluded that venlaflaxine evaluated during a 4 weeks period is effective in reducing hot flushes in breast cancer survivors. The 75 mg venlaflaxine dose resulted in a 60% reduction in hot flushes, while the 37.5 mg dose attended only a 40% reduction; however, the higher dose was responsible for greater side effects, including nausea, mouth dryness, constipation, and appetite suppression. The aim of our open-label study was to evaluate the efficacy and tolerability of a longer treatment (8 weeks) with the same low dose of venlaflaxine in the reduction of hot flushes activity in postmenopausal patients with breast cancer.

3 80 N. Biglia et al. / Maturitas 52 (2005) Methods Forty consecutive patients attending the outpatient clinic for menopause symptoms entered the study after giving written informed consent. All patients had suffered from breast cancer in the past and had been operated at least 1 year before. Inclusion criteria were: the presence of troublesome hot flushes, occurring for at least 20 times a week and present for at least 3 months before study entry, age between 18 and 70 years, absence of documented metastasis. There was no requirement that a patient had to fulfill any menopausal status criteria. Exclusion criteria were: use of antidepressant treatment within the last 6 months; use of progestagens or any other medication to treat hot flushes within the previous 6 months, concomitant chemotherapy, uncontrolled hypertension (diastolic blood pressure > 95 mmhg, systolic blood pressure > 160 mmhg, or both), diabetes. Antiestrogen therapy (tamoxifene, aromatase inhibitors and GnRh analogues) was allowed, provided that it had been started at least 4 months before study entry and continued for the next 3 months. Women received venlaflaxine XR 37.5 mg/day for 8 weeks. No therapy was started during the first week and the patient was asked to complete daily hot flushes diary pointing out the number of the vasomotor events and their severity subdivided into mild, moderate, severe and very severe. Each degree of severity corresponded to a number (1 4) and the daily score was calculated multiplying the daily frequency of hot flushes by these numbers and adding together the four numbers. This type of questionnaire was already used in a series of previous trials inquiring about hot flushes and its validity was proved [27]. The hot flushes dairy was filled in during the next 8 weeks of therapy. At the end of each week of drug assumption, patients had to evaluate side effects such as nausea, mouth dryness, constipation, tiredness, nervousness, sleepiness and dizziness on a scale ranging their intensity between 1 and 4. Libido was evaluated at baseline and every week during the study using a scale ranging from 0 (absence of sexual interest) to 3 (high sexual satisfaction). A Beck Depression Inventory (BDI) was completed at baseline (no therapy) and at the end of the 8 weeks therapy [28]. At weeks 4 and 8 a clinical visit was performed in order to measure blood pressure and to assess side effects and hot flushes frequency. The patient had to be excluded from the study if diastolic pressure was found above 95 mmhg and systolic pressure above 160 mmhg or if important side effects occurred. 3. Statistical consideration The primary end point of this study was to compare the basal value of hot flushes frequency (the number of hot flushes reported per day) and a hot flushes score with the results after 4 and 8 weeks of treatment. Dependent samples t-test was used to analyze data and Shapiro Wilk test to confirm that the sample is from a normal population. When normality of data was not confirmed, the Wilcoxon Signed Rank test was used. Secondary end points included the incidence of each toxicity reported in the treatment period. SPSS software was used for statistical analysis. Statistical significance was determined by using an alpha level of 0.05 and two-sided tests. 4. Results Between January 2002 and September 2003, 40 patients were included in the study. During the first week, five patients decided to withdraw from the trial and never began the therapy. Of the remaining 35 women who entered into the study and started the drug, only 30 patients had correctly taken venlafaxine and had completed the daily hot flushes diary during the first month of therapy. Three additional patients dropped out during the second 4-week treatment period. No patient was withdrawn by physicians for blood pressure increase or important toxicity. Among the 13 patients who withdrew from the trial, 8 did it spontaneously, or sometimes advised by friends, relatives or general practitioners, because of fear of beginning or carring on a new therapy after having been cured of their breast cancer event. Three patients, one during the first 3 weeks of therapy and two during the next 5 weeks were satisfied with the resolution of hot flushes and stopped the therapy. Only two women

4 N. Biglia et al. / Maturitas 52 (2005) Table 1 Patients characteristic at baseline No. of patients Age years 14 (35%) >49 years 26 (65%) Hot flushes duration <9 months 15 (36%) >9 months 25 (64%) Daily hot flushes frequency 3 3 (12%) (40%) >9 21 (48%) Tamoxifen use Users 26 (65%) Not users 14 (35%) Mean BDI score Mean 8 (23 cases) 95%CI Mean weekly hot flushes frequency Mean %CI Range Mean weekly hot flushes score Mean %CI Range after the first week of therapy reported troublesome side effects, mostly gastroenteric, and stopped the treatment. Table 1 lists the baseline characteristics of the patients in terms of age, tamoxifene use (64.4%), hot flushes activity and Beck Depression Inventory scores. Table 2 shows changes in weekly hot flushes frequency and weekly hot flushes score after 4 and 8 weeks of drug assumption. At week 4, the 30 patients taking venlaflaxine reported a significant reduction of weekly hot flushes number, 39% lower than baseline (p < 0.001) Table 3 Hot flashes modification at 4 and 8 weeks HF frequency Table 2 Mean hot flushes activity after 4 and at 8 weeks Mean hot flashes number/week Baseline 80.4 (40 pts) At 4 weeks 47.5 (30 pts) Reduction at 4 weeks 30.5 ( 39.1%) % Reduction 39.1% p <0.001 At 8 weeks 36.0 (27 pts) Reduction at 8 weeks 41.2 % Reduction 53.3% p <0.001 Mean hot flashes score Baseline (40 pts) At 4 week (30 pts) Reduction at 4 weeks 82.4 % Reduction 41.7% p <0.001 At 8 week (27 pts) Reduction at 8 weeks % Reduction 59.7% p <0.001 and a 41.7% reduction in the weekly hot flushes score (p < 0.001). At week 8 (27 patients), a further significant reduction was observed for the hot flushes weekly frequency ( 53.3% p < 0.001) and for the hot flushes weekly score ( 59.7% p < 0.001) compared to baseline. Table 3 lists the distribution of patients whose hot flushes activity decreased by varying amounts over the two treatment periods. After the first month of therapy, 47% of patients taking venlaflaxine experienced a reduction in hot flushes score ranging from 25 to 50%, and 33% of them a reduction greater than 50% as compared to basal values. At week 8, the majority of them (70%) showed a reduction greater than 50%. Similar results were observed for the hot flushes frequency. HF score At 4 weeks (30 pts) At 8 weeks (27 pts) At 4 weeks (30 pts) At 8 weeks (27 pts) Worsening 1 (3%) 1 (4%) 1 (3%) 1 (4%) <25% reduction = placebo 6 (20%) 4 (15%) 5 (17%) 4 (15%) 25 50% reduction 15 (50%) 4 (15%) 14 (47%) 3 (11%) >50% reduction 8 (27%) 18 (66%) 10 (33%) 19 (70%)

5 82 N. Biglia et al. / Maturitas 52 (2005) Concerning BDI to asses depression symptoms, it was completed both at week 0 and 8 only by 23 patients. The mean BDI baseline score was 8.0 (95%CI: ); only one of the women may be classified as having a mild depression. Depression score improved by an average of 1.9 points after 8 weeks of therapy (mean score 6.1; 95%CI: ), with a significant reduction of 23% as compared to pretreatment value (p < 0.001, a lower score indicate fewer depressive symptoms). Sporadic side effects were reported, mostly nausea and mouth dryness. Fifteen percent of patients experienced nausea, a significant 10% increase was recorded at the end of the first week of assumption, and this score was already halved after the second week. From week 3 on, nausea had largely disappeared. Mouth dryness was reported by 6% of patients. It was a very light side effect that promptly vanished after week 2. Libido scores improved from baseline since week 1 by 20% and maintained a plateau during the following weeks of therapy. 5. Discussion Hot flushes are a very important problem for breast cancer survivors. While in normal aging a gradual lowering of estrogens occurs, in these patients there is often a rapid change in the hormonal menopause status. The cause of this sudden change in younger patients is usually due to the use of chemotherapy that is frequently associated with either temporary or permanent amenorrhea [29]. Alkylating agents, such as cyclophosphamide, appear to be associated with a major incidence of amenorrhea than regimens involving other drugs, for example, antracycline. The cumulative dose of chemotherapy and the age of the patient are two additional variables that influence the incidence of ovarian failure, younger women are less likely to have amenorrhoea induced by chemotherapy than women over 40, who frequently to have permanent ovarian dysfunction. Breast cancer patients often require adjuvant therapy with tamoxifene that worsens but hot flushes and night sweats [30]. Even if vasomotor symptoms induced by tamoxifen frequently become less pronounced after 3 6 months of therapy, they still remain a heavy cause of psychosomatic distress in these patients and they can be the cause of normal activity disruption [31]. Women who had previously suffered from severe hot flushes during natural menopause or who had previously experienced HT complain much more for intense hot flushes. Despite the prevalence of the symptoms, the pathophysiology of hot flushes remains unknown. A decline in hormone concentrations might lead to alterations in brain neurotransmitters and to instability in the hypothalamic thermoregulatory set point. Hot flushes are known to involve a rise in core body temperature, vasodilatation and diaphoresis at least partially due to estrogen withdrawal. Estrogens therapy is considered contraindicated in breast cancer survivors because of concerns about potential recurrence of cancer [6]. Several trials have investigated many antidepressant agents as potential therapy for the control of hot flushes [16 20,22,25,26]. It bears noting that the placebo effect is higher in trials of hot flushes than for many other conditions. In well-controlled, randomized clinical trials placebo treatment has reduced hot flushes activity by 27 37% in women with a history of breast cancer [16,17,26]. Our study lack of a control arm, but the results obtained after 8 weeks of treatment with venlafaxine are higher than those obtained in all the controlled trials using placebo in breast cancer patients. Also, the potential confounding effect of the physiological abatement of hot flushes seen over time is very unlike in a short period of time. The optimal duration of the treatment is debated, in controlled trials using antidepressant drugs with the aim of controlling hot flushes; a short period ranging from 4 to 6 weeks of therapy is considered. This duration was chosen because the reduction in hot flushes with venlafaxine appears suddenly during the first or second week of therapy and then a plateau is reached during the following 2 weeks. Loprinzi et al. [26] showed that venlaflaxine efficacy in reducing the hot flushes severity is dosedependent. In this trial patients were randomised to receive placebo or venlaflaxine at a dose of 37.5, 75 or 150 mg/day for 4 weeks. Patients in all four-treatment subsets experienced a subjective improvement in their symptoms, ranging from a 25% reduction in hot flush score for patient on placebo to a 61% reduction for those taking 75 mg venlaflaxine each day. The 75 mg venlaflaxine dose was significantly more effective than 37.5 mg dose, which only reduced hot flush score by 37%, but not less effective than 150 mg. A continuation phase of this trial was designed to allow weekly dose

6 N. Biglia et al. / Maturitas 52 (2005) adjustments based on patients response; on average, patients initially assigned to the highest venlafaxine arm (150 mg/day) tended to lower their doses, while patients initially assigned to the 37.5 mg/day arm tended to increase their doses up to a mean dose of 75 mg/day [32]. Based on this data Loprinzi et al. recommended that venlafaxine therapy for hot flushes be initiated at a dose of 37.5 mg/day, increasing to 75 mg/day after 1 week if the control is not optimal [24]. Although venlaflaxine was generally well tolerated, 75 mg caused more side effects (nausea, anorexia, mouth dryness, constipation) than the 37.5 mg dosage; doses in excess of 75 mg/day have greater toxicity, but do not appear to have greater efficacy than 75 mg/day. Up to date, few data are available on what happens during the following weeks if therapy is continued at low doses. In our study, we decided to test low-dose venlaflaxine during an 8 weeks period to evaluate if the continuation of therapy could produce a greater benefit, minimizing side effects reported with standard 75 mg/day dose. Hot flush activity was reduced by 40% at week 4 and continuing the therapy for one additional month at the same dose, a 60% decrease in the H.F. score compared to baseline was obtained. Nausea was the major complaint for patients taking venlaflaxine. This symptom promptly appeared during the first week of therapy in 15% of patients and was cause of dropping out of the study for two of them; it disappeared in the vast majority of patient over the following weeks of therapy. Nausea can be minimized with low starting doses and administration of the medication with meals; sometimes, a temporary (2 3 weeks) low dosage of substituted benzamides (such as levosulpiride 25 mg/day) can be used to avoid the venlafaxine discontinuation in the first period of treatment or to allow a dosage increase in patients non responding to 37.5 mg and needing 75 mg/day. As measured by the Beck Depression Inventory, mood improved by 23%. Moreover, in our sample, the mean BDI baseline score ranged between 6.5 and 9.7, always below the cut-off accepted for depression with the exception of one case. On the other hand, scores near 10 can point-out a risk of subthreshold depression that in oncological population can easily shift to conclamate depression cancer symptoms develop. Therefore, besides the anti-hot flushes activity, any adjunctive antidepressant and anxiolitic effect of venlafaxine can be welcomed in these women. Libido worsening is a frequent symptom in menopausal women and SSRIs, because of their pure serotoninergic activity, can further increase sexual problems, for example, producing orgasm delays. Venlafaxine, due to its additional noradrenergic activity, has a lower incidence of sexual dysfunction than SS- RIs. Even if a complete evaluation of sexual function by specific and validated questionnaires was not performed in this study, a simple score of libido was evaluated weekly showing no significant change of sexual interest during the treatment period, also if in the first weeks of therapy a modest, not significant, improvement (20%) of the score was noted. An issue that has to be considered is the safety of antidepressants drugs in breast cancer survivors. Recent reports of mammoplasia during SSRIs therapy suggested that this side effect might be more common than previously reported. Amsterdam et al. [33] examined women receiving two or more month s treatment with an SSRI or venlafaxine for changes in breast size. The safety of venlafaxine at this regard was demonstrated by the observation that, among the 23 out of 59 patients (39%) reporting some degree of mammoplasia, the ones treated with venlafaxine demonstrated significantly lower incidence of mammoplasia (p < 0.01) than those treated with SSRIs. Recently, Stearns et al. have identified a potentially important interaction between the SSRI paroxetine and tamoxifen [34]. Tamoxifen is converted to 4-hydroxytamoxifen and other active metabolites by cytochrome P450 enzymes and it has been hypothesized that the coadministration of tamoxifen and SSRIs might alter the metabolism of this drug. Infact, the newer antidepressants studied for the treatment of hot flushes, are all metabolized by cytochrome P4502D6 and may inhibit this enzyme [14]. Coadministration of paroxetine and tamoxifen decreased plasma concentration of endoxifen, but none of the other metabolites underwent significant changes in concentration. In an editorial on the same issue, Goetz and Loprinzi notice that the clinical implications of reduced levels of endoxifen are yet unclear [35]. Infact, it has been widely believed that the clinical activity of tamoxifen is largely mediated by another metabolite, 4-hydroxy-tamoxifen, whose levels are unmodified by paroxetine in this study. A recent study on breast cancer cell lines has demonstrated that endoxifen has equivalent activity to the potent metabo-

7 84 N. Biglia et al. / Maturitas 52 (2005) lite 4-OH-tamoxifen and plasma levels often exceeding the levels of 4-OH-tamoxifen. These data suggest that endoxifen and 4-OH-tamoxifen may be essentially equivalent, but prospective clinical studies are required in order to evaluate the impact of tamoxifen metabolims on therapeutic outcome [36]. However, the newer antidepressants have different levels of CYP2D6 inhibition and in vitro studies suggest that venlafaxine is a much weaker inhibitor of CYP2D6 than fluoxetine and paroxetine, whereas mirtazapine does not inhibit this enzyme at all [14]. 6. Conclusion In conclusion, low dose venlafaxine can be recommended for the treatment of hot flushes in patients previously treated for breast cancer. A treatment duration of 8 weeks produces a significant improvement in hot flushes severity and is associated with little side effects. Data on the safety of this therapy on breast cancer prognosis are reassuring. 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