30 April 2012:

The selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants are used off-label to treat menopausal hot flushes. One of their most common side-effects is insomnia and, therefore, investigation of this mode of therapy in postmenopausal women with vasomotor symptoms and related sleep disturbances is of importance. The aim of a recent randomized, blinded, multicenter, placebo-controlled study was to determine the effect of escitalopram, a widely used SSRI, on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flushes [1].

The study included 205 women (95 African-American, 102 white, eight other) who received escitalopram (10–20 mg/day) or placebo for a duration of 8 weeks. Insomnia symptoms (Insomnia Severity Index, ISI) and subjective sleep quality (Pittsburgh Sleep Quality Index, PSQI) at weeks 4 and 8 were the pre-specified secondary outcomes. A total of 199 women (97%) provided ISI data and 194 (95%) women provided PSQI data at follow-up. At baseline, the mean hot flush frequency was 9.8 per day (standard deviation (SD) 5.60), the mean ISI was 11.4 (SD 6.3), and the mean PSQI was 8.0 (SD 3.7). Treatment with escitalopram reduced the ISI at week 8 (mean difference -2.00; 95% confidence interval (CI) -3.43 to -0.57; p < 0.001, overall treatment effect), with mean differences of -4.73 (95% CI -5.72 to -3.75) in the escitalopram group and -2.73 (95% CI -3.78 to -1.69) in the placebo group. The reduction in PSQI was greater in the escitalopram group than in the placebo group at week 8 (mean difference -1.31; 95% CI -2.14 to -0.49; p < 0.001, overall treatment effect). Clinical improvement in insomnia symptoms and subjective sleep quality (≥ 50% decreases in ISI and PSQI from baseline) was observed more frequently in the escitalopram group than in the placebo group (ISI: 50.0% vs. 35.4%, p = 0.04; PSQI: 29.6% vs. 19.2%, p = 0.09). The investigators' conclusions were that. among healthy perimenopausal and postmenopausal women with hot flushes, escitalopram at 10–20 mg/day compared with placebo reduced insomnia symptoms and improved subjective sleep quality at 8 weeks of follow-up.

Comment

Data on the ability of antidepressants to reduce the frequency and severity of hot flushes are abundant. In its recently published review on vasomotor symptoms, the International Menopause Society allocated a section to treatment by SSRIs, SNRIs and gabapentin [2]. A phrasing from that section said that 'in general, these preparations reduce the frequency and severity of hot flushes by 50–60%', whereas 'in comparison, standard-dose estrogen reduces hot flushes by 80–90%'. Note that the same group who has now reported on the effects of escitalopram has already published a year ago their same data in regard to the reduction in hot flushes [3]. Their conclusion was as follows: 'Escitalopram 10–20 mg/day provides non-hormonal off-label treatment for menopausal hot flushes that is effective and well-tolerated in healthy women.' In my view, while the IMS clearly stated that SSRIs and SNRIs should be prescribed to symptomatic women who choose not to take HRT, or have contraindications for HRT – and thus a second-line therapy, many physicians are wrong in addressing antidepressants as a first-line option. As an excuse, they put forward the shifts in the risk–benefit ratio for HRT identified by the Women's Health Initiative. However, several major points are overlooked.

First, the risks of HRT in young postmenopausal women, for at least the first 5–7 years of treatment, are negligible or non-existing. The perimenopausal and early postmenopausal period is actually the critical time to treat vasomotor symptoms, and the state-of-the-art clinical data, including those from the WHI trial, clearly demonstrate a safe profile for HRT, on the one hand, with a very high efficacy in regard to reduction of symptoms on the other hand. Escitalopram was able to decrease the frequency of hot flushes only by 47% as compared to placebo, which induced a 33% decrease [3]. The difference was thus about 14%, which corresponds to only 1–2 fewer hot flushes per day. Similar results were recorded for the sleep quality and insomnia scores. Perhaps such an effect is significant for women who have no alternatives (i.e. breast cancer patients), but certainly antidepressants should not be used instead of HRT.

Second, the escitalopram study lasted only 8 weeks, while therapy for hot flushes is much longer term, and thus we are not able to know whether several months or years of therapy will maintain the same effect. With HRT we do have such long-term follow-up data.

Third, while the serious HRT-related adverse events are always put forward in any forum, debate or paper, the corresponding short- and long-term side effects of SSRIs/SNRIs are somewhat downgraded. Even in the current study, which lasted only 8 weeks, seven women in the treatment group, and only two in the placebo group stopped treatment due to adverse events [1]. Review of the list of adverse events of SSRIs reveals that therapy might be associated with suicidality, episodes of mania and panic disorder, decreased libido, weight gain and many other disorders [4]. Special attention should be given to cessation of therapy, since abrupt discontinuation may lead to severe withdrawal symptoms. The position of the International Menopause Society has always been that HRT remains the best and most effective treatment of vasomotor symptoms. Alternative, less effective therapies should be considered only in women who have a contraindication to HRT or in those who do not wish to take HRT.

Amos Pines

Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel

References

1. Ensrud KE, Joffe H, Guthrie KA, et al. Effect of escitalopram on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes: a randomized controlled trial. Menopause 2012 Mar 19. Epub ahead of print. http://www.ncbi.nlm.nih.gov/pubmed/22433978

2. Archer DF, Sturdee DW, Baber R, et al. Menopausal hot flushes and night sweats: where are we now? Climacteric 2011;14:515-28. http://www.ncbi.nlm.nih.gov/pubmed/21848495

3. Freeman EW, Guthrie KA, Caan B, et al. Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial. JAMA 2011;305:267-74. http://www.ncbi.nlm.nih.gov/pubmed/21245182

4. Cipralex leaflet. http://www.alpha-med.co.il/WEB/8888/NSF/Web/5414/Cipralex.pdf