Q&A 221.5

What evidence is available for the use of antidepressants for the management of menopausal hot flushes?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

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Date prepared: 13th May 2014

Background

This is the first of two Medicines Q&As addressing the management of menopausal hot flushes with non-hormonal drug therapy. The other Medicines Q&A No.222: “What non-hormonal alternatives to antidepressants are available for the management of menopausal hot flushes?” is available here.

Hot flushes (or flashes) are the most common symptom of the menopause and may be experienced by more than 50% of menopausal women. Until recently, hormone replacement therapy (HRT) was widely used to alleviate hot flushes. However, following the publication of the Women’s Health Initiative study in 2002, together with other more recent studies reporting adverse effects of oestrogen, alternative non-hormonal treatments are now being considered (1).

Answer

Lifestyle advice

To help reduce hot flushes, women should be encouraged to take regular exercise, reduce stress and wear lighter clothing. Any trigger factors (e.g. caffeine, alcohol, smoking, spicy foods) should also be avoided (2).

Non-hormonal treatment options

If lifestyle modifications prove ineffective, then other treatments may be considered (2).

However, it should be noted that a placebo response rate of 18-40% has been observed in hot flush clinical trials, so the true effect of treatment may be difficult to establish. In addition, many of the trials have been conducted in women with a history of breast cancer. In this patient population, worsening hot flushes may be associated with rapidly declining oestrogen levels as well as adverse effects of chemotherapy, radiation and anti-oestrogens e.g. tamoxifen (3).

Antidepressant Medications

Antidepressants are unlicensed in the UKfor the management of hot flushes, but may be considered for women who have contra-indications to or concerns about HRT (2). Limited evidence from a 2006 meta-analysis suggests that venlafaxine, paroxetine, citalopram or fluoxetine are effective in reducing the frequency and severity of menopausal hot flushes (1,2). Studies have also been conducted using moclobemide (1), sertraline (4,5), duloxetine (6,7) and escitalopram (8,9)which have produced variable results (see Table). However, most of these studies have been short-term, and the long-term efficacy is not known (3).

Relief from hot flushes with selective serotonin re-uptake inhibitors (SSRIs) and venlafaxine is typically achieved at lower doses and more rapidly compared with the management of depression. A short-term trial of 1-2 weeks may be adequate to assess the effect of an SSRI (3 weeks for fluoxetine) or venlafaxinefor hot flushes (10). A low dosage of antidepressant should be used initially, which should be titrated according to effect. The most appropriate dosage and duration of treatment has not been established (3).

Whilst no withdrawal reactions have been reported when used for the short-term treatment of hot flushes (11), it is advisable to stop treatment cautiously by tapering off the antidepressant to prevent discontinuation syndrome (10,11,12).

The Royal College of Obstetricians and Gynaecologists suggests that the most convincing data available are for venlafaxine at a dose of 37.5mg twice daily. Further trials are needed to confirm efficacy and long-term safety (13).

Examples of key studies assessing the use of antidepressants for treatment of hot flushes.

Intervention / Report descriptions [ref] / Dose of intervention / Outcome vs placebo / Comments
Paroxetine / Systematic review
(2 RCTs)* [1] / 1. Paroxetine controlled release12.5mg/day or 25mg/day (n=165)
2. Paroxetine 10mg/day or 20mg/day (n=151) / Fewer‡ daily hot flushes. Composite scores† reduced‡. / More adverse effects e.g. headache, nausea seen at higher doses.
Venlafaxine / Systematic review
(2 RCTs)* [1] / 1. Venlafaxine extended release 37.5mg, 75mg or 150mg/day (n=221)
2. Venlafaxine extended release 75mg/day (n=80) / 1. Decreased‡ hot flush frequency and composite scores†.
2. No difference in frequency or composite score†. / Adverse effects e.g. dry mouth, nausea, decreased appetite, constipation more common at higher doses.
Monitor blood pressure [10].
Fluoxetine / Systematic review
(2 RCTs)* [1] / 1. Fluoxetine 20mg/day (n=81)
2. Fluoxetine 30mg/day vs citalopram 30mg/day (n=150).Starting doses of 20mg/day increased at 6 months for both drugs. / 1. No significant difference in hot flush frequency or composite score†
2. No significant difference in hot flush frequency and Kupperman Index scores# / 2. Main adverse effects included nausea and dry mouth.
SSRI or SNRI (serotonin and noradrenaline re-uptake inhibitor) / Meta-analysis (seven comparisons from 6 RCTs above)* [1] / Paroxetine controlled release12.5mg/day or 25mg/day (1 trial), paroxetine 10mg/day or 20mg/day (1 trial)
Venlafaxine extended release 37.5mg/day, 75mg/day (2 trials)
Fluoxetine 20mg/day (2 trials)
Citalopram 20mg/day (1 trial) / Combined weighted mean difference in no. of daily hot flushes was -1.13 (95%CI, -1.70 to
-0.57) / Main disadvantage (particularly SNRIs) is high incidence of nausea, which may lead to treatment withdrawal before optimum effect can be achieved [12].Reduced libido and sexual response also reported [12].
Moclobemide / Systematic review
(1 RCT) [1] / Moclobemide 150mg/day or 300mg/day (n=30) / Comparison with placebo not reported. / Poor quality RCT. Two withdrawals due to somnolence.
Sertraline / (a)RCT [4]
(b) RCT [5] / (a) Sertraline 50mg/day (n=97)
(b) Sertraline 50mg/day for 2 weeks then 100mg/day (n=99) / (a) Modest reduction‡ in hot flush frequency and composite score†. No difference in severity.
(b) No significant difference in hot flush frequency or severity score / (a) Nausea reported. Variable treatment response.
(b) Worsened sexual function and dry mouth reported.

See end of table for key

Table (continued)

Citalopram / (a) Systematic review
(1 RCT) [1]
(b) Single-blind study, four arms including HRT [14]
(c) RCT* [15] / (a) See fluoxetine above
(b) Citalopram final dose range 20-40mg/day (n=100)
(c) Citalopram final dose range 10-30mg/day (n=254) / (a) See fluoxetine above
(b) Hot flush scores significantly reduced‡
(c) Hot flush severity score significantly reduced‡ (based on 196 evaluable patients) / (b) Somnolence, increased perspiration, palpitation, dry mouth reported.
(c) Tendency for more adverse effects with 30mg/day dose so not recommended.
Escitalopram / (a) RCT [8]
(b) Two RCTs [9] / (a) Escitalopram final dose 10mg or 20mg/day (n=205)
(b) (i) Preliminary study (n=16): escitalopram 10mg/day (ii) Second study (n=26): escitalopram 20mg/day / (a) Significant reduction‡ in hot flush frequency and severity
(b) No effect on objectively recorded hot flush frequency at either 10mg or 20mg/day / (b) Well tolerated.
Duloxetine / (a)Open label study. No placebo arm [6]
(b)Open label study. No placebo arm.[7] / (a) Duloxetine final dose range 60mg-120mg/day (n=20;patients also had major depressive disorder)
(b) Duloxetine final dose 60mg/day (n=19);patients also had major depressive disorder / (a) Vasomotor symptom score improved compared to baseline (secondary outcome).
Primary outcome was improved symptoms of depression
(b) Vasomotor symptom score improvedcompared to baseline (secondary outcome).
Primary outcome was improved symptoms of depression / (a) Common side effects included constipation, headache, dry mouth. Withdrawals (n=3) due to nausea, difficulty concentrating, intrusive thoughts.
(b) Withdrawals due to nausea, headache, dizziness (n=1),and possible drug rash (n=1).

* some studies included patients with a history of breast cancer, or active breast cancer +/- anti-oestrogens

‡ difference vs placebo was statistically significant (p<0.05)

formulation not available in the UK

† composite score = frequency x severity

RCT = randomised controlled trial

# Kupperman Index = menopausal symptom score

General Advice

As data are limited, it has been suggested that the use of non-hormonal treatments for menopausal hot flushes should be restricted to highly symptomatic women who cannot take oestrogen (1). Due to the variability in the assessment methods used in studies to assess hot flushes, comparisons between study results are difficult (10). Larger, more standardised head-to-head and placebo-controlled trials are needed to establish the efficacy and safety of these treatment options (1).

Symptom severity, medical history and concomitant drug treatment should be considered when selecting the most appropriate therapy (3).

This Medicines Q&A has not addressed drug interactions. However, a recent population based study in women taking tamoxifen and an SSRI (n=2430) indicated that the risk of death from breast cancer increased with the length of concomitant treatment with paroxetine, but not with other SSRIs.Tamoxifen is a prodrug which is metabolised to an active metabolite by cytochrome P450 isoenzyme 2D6 (CYP2D6) and SSRIs inhibit this enzyme to varying degrees (16). It has therefore been suggested that strong CYP2D6 inhibiting SSRIs (e.g. paroxetine, fluoxetine) should be avoided in women taking tamoxifen (17). This advice has been confirmed by the Medicines and Healthcare products Regulatory Agency (MHRA) in a recent Drug Safety Update bulletin (18). However, further studies are needed (17).

Currently no data support the use of more than one treatment concomitantly for the management of hot flushes. Clinicians should continuously review efficacy of treatment and assess whether an alternative treatment is necessary (12).

Summary

To help reduce hot flushes, women should be encouraged to take regular exercise, reduce stress and wear lighter clothing. Any trigger factors should be avoided (2).

Antidepressants are unlicensed in the UK for the management of hot flushes, but may be considered for women who have contra-indications to or concerns about HRT (2). Limited evidence from a 2006 meta-analysis suggests that venlafaxine, paroxetine, citalopram or fluoxetine are effective in reducing the frequency and severity of menopausal hot flushes (1,2).

Relief from hot flushes with selective serotonin re-uptake inhibitors (SSRIs) and venlafaxine is typically achieved at lower doses and more rapidly compared with the management of depression. A short-term trial of 1-2 weeks may be adequate to assess the effect of an SSRI (3 weeks for fluoxetine) or venlafaxine for hot flushes (10). A low dosage of antidepressant should be used initially, which should be titrated according to effect. The most appropriate dosage and duration of treatment has not been established (3).

The Royal College of Obstetricians and Gynaecologists suggests that the most convincing data available are for venlafaxine at a dose of 37.5mg twice daily. Further trials are needed to confirm efficacy and long-term safety (13).

Studies have also been conducted using moclobemide (1), sertraline (4,5), duloxetine (6,7) and escitalopram (8,9) which have produced variable results.

Most of these studies have been short-term, and the long-term efficacy of non-hormonal treatment for hot flushes is not known (3). As data are limited, it has been suggested that their use should be restricted to highly symptomatic women who cannot take oestrogen (1).

This Medicines Q&A has not addressed drug interactions. However, it has recently been suggested that strong CYP2D6 inhibiting SSRIs (e.g. paroxetine, fluoxetine) should be avoided in women taking tamoxifen (17,18).

Clinicians should continuously review efficacy of treatment and assess whether an alternative treatment is necessary (12).

Limitations
The following treatment options have not been considered in this Medicines Q&A:

  • Complementary and alternative medicines.
  • Dietary supplements
  • Formulations not available in the UK

The non-hormonal management of cancer treatment induced menopause was specifically not researched for this Medicines Q&A. However, some of the meta-analyses, systematic reviews and other review articles cited have included women with a history of cancer, or active cancer and/or drug-induced hot flushes. The applicability of the findings of these studies to the general population of menopausal women has not been definitively demonstrated (19).

Only examples of the key studies assessing the efficacy of non-hormonal treatments for the management of hot flushes have been included in this Medicines Q&A. Case reports and pilot studies have been excluded.

Although comparative studies with hormone replacement therapy have been included in the table, the HRT component has been excluded from the evaluation.

References

  1. Nelson HD, Vesco KK, Haney E et al. Nonhormonal therapies for menopausal hot flashes:systematic review and meta-analysis. JAMA 2006;295(17):2057-2071.
  2. NICE Clinical Knowledge Summaries. Managing the menopause without HRT. Accessed via 13th May 2014.
  3. Carroll DG. Nonhormonal therapies for hot flashes in menopause. Am Fam Physician 2006;73(3):457-464.
  4. Gordon PR, Kerwin JP, Boesen KG et al. Sertraline to treat hot flashes: a randomized controlled, double-blind, crossover trial in a general population. Menopause 2006;13(4):568-575.
  5. Grady D, Cohen B, Tice J et al. Ineffectiveness of sertraline for treatment of menopausal hot flushes: a randomized controlled trial. Obstet Gynecol 2007;109:823-30.
  6. Joffe H, Soares CN, Petrillo LF et al. Treatment of depression and menopause-related symptoms with the serotonin-norepinephrine reuptake inhibitor duloxetine. J Clin Psychiatry 2007;68:943-950.
  7. Freeman MP, Hirschberg AM, Wang B et al. Duloxetine for major depressive disorder and daytime and nighttime hot flashes associated with the menopausal transition. Maturitas 2013;75:170-174.
  8. 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(3):267-274.
  9. Freedman RR, Kruger ML, Tancer ME. Escitalopram treatment of menopausal hot flashes. Menopause 2011;18(8):893-896.
  10. Carroll DG, Kelley KW. Use of antidepressants for management of hot flashes. Pharmacotherapy 2009;29(11):1357-1374.
  11. Albertazzi P. Non-estrogenic approaches for the treatment of climacteric symptoms. Climacteric 2007;10 (Suppl 2):115-120.
  12. Stearns V. Clinical update: new treatments for hot flushes. Lancet 2007;369:2062-2064.
  13. Scientific Advisory Committee Opinion Paper 6 (2nd Edition). Alternatives to HRT for the management of symptoms of the menopause.RoyalCollege of Obstetricians and Gynaecologists. September 2010 Accessed via 13th May 2014.
  14. Kalay AE, Demir B, Haberal A et al. Efficacy of citalopram on climacteric symptoms. Menopause 2007;14(2):223-229.
  15. 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;28(20):3278-3283.
  16. Kelly CM, Juurlink DN, Gomes T et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010;340:c693 doi:10.1136/bmj.c693.
  17. Andersohn F, Willich SN. Interaction of serotonin reuptake inhibitors with tamoxifen. BMJ 2010;340:c783 doi:10.1136/bmj.c783.
  18. Medicines and Healthcare products Regulatory Agency (MHRA). Drug Safety Update November 2010;4(4):A1.
  19. Santoro N. Symptoms of menopause:hot flushes. Clin Obstet Gynecol 2008;51(3);539-548.

Quality Assurance

Prepared by

Nicola Watts, Medicines Information Pharmacist (based on earlier work by Kate Pickett), Wessex Drug and Medicines Information Centre, University Hospital Southampton NHS Foundation Trust.

Date Prepared

13th May 2014

Checked by
Kate Pickett, Medicines Q&A Pharmacist (based on the Q&A originally checked by Samantha Owen),Wessex Drug and Medicines Information Centre, University Hospital Southampton NHS Foundation Trust.

Date of check

11th June 2014

Search strategy

  • Medline via NICE Evidence Search: exp HOT FLASHES/dt AND exp MENOPAUSE/ (Limits: LG=EN, H=Y, 2005-current)
  • Embase via NICE Evidence Search: exp HOT FLUSH/dt AND exp MENOPAUSE/ (Limits: LG=EN, H=Y, 2005-current)
  • Electronic medicines compendium. Accessed via
  • NICE Clinical Knowledge Summaries. Accessed via
  • NICE Evidence. Accessed via
  • British Menopause Society website. Accessed via
  • International Menopause Society website. Accessed via
  • Royal College of Obstetricians and Gynaecologists website. Accessed via
  • Cochrane database. Accessed via

1

Available throughNICE Evidence Search at