Menopause Live (12 July, 2010) from IMS 

For women with hot flushes who are not able to take hormone replacement therapy (HRT) and especially those who are having treatment for breast cancer, the lack of effective alternative therapies remains a difficult problem. Women taking tamoxifen or aromatase inhibitors will often experience severe vasomotor symptoms, which persist for at least as long as the treatment is continued. The possible role of central neurotransmitters in the causation of the hot flush has prompted randomized, placebo-controlled trials of serotinergic antidepressants, with paroxetine, fluoxetine and venlafaxine demonstrating at least a 50% reduction in flushes, but it is unlikely that these are showing a class effect. However, there are now concerns about the use of paroxetine and fluoxetine, due to their potent inhibition of CYP2D6, which is an essential component in the biotransformation of tamoxifen to the potent antiestrogen endoxifen [1]. So there is an urgent need for alternative treatments in this population.

Citalopram, an antidepressant similar to fluoxetine and paroxetine, is a selective serotonin re-uptake inhibitor (SSRI) that is readily absorbed following oral ingestion, reaching a peak serum concentration in 2–4 hours, and, although it is a weak inhibitor of the CYP2D6 pathway, it does not interfere with tamoxifen metabolism in a clinically significant way. Debra Barton and colleagues have conducted a placebo-controlled trial to evaluate three doses of citalopram (10, 20 and 30 mg) for the treatment of hot flushes [2]. A total of 254 patients were randomly assigned, with a two-to-one chance of receiving active agent compared to placebo, and were studied over 6 weeks. The entry criteria included at least 14 bothersome hot flushes per week. The results showed a significant improvement in hot flushes with citalopram over placebo, with no significant differences between doses. Reductions in mean hot flush scores were 2.0 (23%), 7.0 (49%), 7.7 (50%), and 10.7 (55%) for placebo and 10, 20 and 30 mg of citalopram, respectively (p ≤ 0.002). Improvement in secondary outcomes, such as the Hot Flush Related Daily Interference Scale, was statistically superior in the 20-mg arm. Citalopram was well tolerated with no significant adverse effects.

Comment
No treatment for hot flushes is as effective as HRT so it is interesting to know how much of a decrease in hot flushes is truly beneficial and will have a positive impact on quality of life. From this study, a daily reduction of approximately 50% was needed for women to perceive general improvements in quality of life. This reduction was more than they found with placebo (25–30%), although many other HRT studies do report a much higher placebo response [3]. There were no changes in mood, although the doses used in this study are generally much less than those used to manage depression and the patients were only selected on the basis of having flushes. 

The most feared adverse effects of SSRIs are negative sexual adverse effects. From other non-menopause-related studies of SSRIs, evaluation of the incidence of sexual changes is complicated by the co-morbidity of depression in the population from which the data are derived. However, this present study does not provide any data to suggest that short-term changes in sexual function occurred due to citalopram.

It is regrettable, though, that this study is of only 6 weeks’ duration and the patients only had 14 or more flushes per week, which is much less than the 6 months’ duration and at least 50 hot flushes per week that regulatory authorities require for proof of efficacy. The authors conclude that citalopram is an effective, well-tolerated agent for the management of hot flushes with no significant dose response above 10 mg, although broader helpful effects appear to be more evident at 20 mg per day. Therefore, this has to be considered as a preliminary study, and a much longer study of women with more severe flushing is required. Other antidepressants such as venlafaxine do not affect the metabolism of tamoxifen [1] and desvenlafaxine may soon be granted a licence for the treatment of flushes. Nevertheless, this study does provide a further potential option for the group of women who probably suffer more than most by having a severe reduction in their quality of life due to frequent hot flushes but without any suitable means of relief.

David Sturdee
Department of Obstetrics & Gynaecology, Heart of England NHS Foundation Trust, Solihull Hospital, Solihull, UK

References
1. Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010;340:c693.
http://www.ncbi.nlm.nih.gov/pubmed/20142325
2. Barton DL, LaVasseur BI, Sloan JA, et al. Phase III, placebo-controlled trial of three doses of citalopram for the treatment of hot flashes: NCCTG Trial N05C9. J Clin Oncol 2010;May 24; Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/20498389
3. MacLennan A, Lester, S, Moore V. Oral estrogen replacement therapy versus placebo: a systematic review. Climacteric 2001;4:58-74.
http://www.ncbi.nlm.nih.gov/pubmed/11379379