Download What evidence is available for the use of antidepressants for the

Medicines Q&As
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
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 13th May 2014
Background
This is the first of two Medicines Q&As addressing the management of menopausal hot flushes with nonhormonal 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 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 metaanalysis 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 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).
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).
1
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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
Paroxetine
Venlafaxine
Report
descriptions
[ref]
Systematic
review
(2 RCTs)* [1]
Systematic
review
(2 RCTs)* [1]
Dose of intervention
Outcome vs
placebo
1. Paroxetine controlled
release12.5mg/day or
25mg/day (n=165)
2. Paroxetine 10mg/day
or 20mg/day (n=151)
1. Venlafaxine extended
release 37.5mg, 75mg or
150mg/day (n=221)
Fewer‡ daily hot
flushes.
Composite
scores† reduced‡.
More adverse effects e.g.
headache, nausea seen at
higher doses.
1. Decreased‡
hot flush
frequency and
composite
scores†.
2. No difference
in frequency or
composite score†.
1. No significant
difference in hot
flush frequency or
composite score†
2. No significant
difference in hot
flush frequency
and Kupperman
Index scores#
Combined
weighted mean
difference in no.
of daily hot
flushes was -1.13
(95%CI, -1.70 to
-0.57)
Adverse effects e.g. dry mouth,
nausea, decreased appetite,
constipation more common at
higher doses.
Monitor blood pressure [10].
Comparison with
placebo not
reported.
(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
Poor quality RCT. Two
withdrawals due to somnolence.
2. Venlafaxine extended
release 75mg/day (n=80)
Fluoxetine
Systematic
review
(2 RCTs)* [1]
SSRI or
SNRI
(serotonin
and
noradrenaline
re-uptake
inhibitor)
Metaanalysis
(seven
comparisons
from 6 RCTs
above)* [1]
Moclobemide
Systematic
review
(1 RCT) [1]
(a) RCT [4]
Sertraline
(b) RCT [5]
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.
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)
Moclobemide 150mg/day
or 300mg/day (n=30)
(a) Sertraline 50mg/day
(n=97)
(b) Sertraline 50mg/day
for 2 weeks then
100mg/day (n=99)
Comments
2. Main adverse effects
included nausea and dry mouth.
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].
(a) Nausea reported. Variable
treatment response.
(b) Worsened sexual function
and dry mouth reported.
See end of table for key
2
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Table (continued)
Citalopram
(a) Systematic
review
(1 RCT) [1]
Escitalopram
Duloxetine
(a) See fluoxetine above
(a) See fluoxetine
above
(b) Singleblind study,
four arms
including HRT
[14]
(b) Citalopram final dose
range 20-40mg/day
(n=100)
(b) Hot flush
scores
significantly
reduced‡
(b) Somnolence, increased
perspiration, palpitation, dry
mouth reported.
(c) RCT* [15]
(c) Citalopram final dose
range 10-30mg/day
(n=254)
(c) Tendency for more adverse
effects with 30mg/day dose so
not recommended.
(a) RCT [8]
(a) Escitalopram final
dose 10mg or 20mg/day
(n=205)
(c) Hot flush
severity score
significantly
reduced‡ (based
on 196 evaluable
patients)
(a) Significant
reduction‡ in hot
flush frequency
and severity
(b) Two RCTs
[9]
(b) (i) Preliminary study
(n=16): escitalopram
10mg/day (ii) Second
study (n=26):
escitalopram 20mg/day
(b) No effect on
objectively
recorded hot
flush frequency at
either 10mg or
20mg/day
(b) Well tolerated.
(a) Open
label
study. No
placebo
arm [6]
(a) Duloxetine final dose
range 60mg-120mg/day
(n=20;patients also had
major depressive
disorder)
(a) Vasomotor
symptom score
improved
compared 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) Open
label
study. No
placebo
arm.[7]
(b) Duloxetine final dose
60mg/day (n=19);
patients also had major
depressive disorder
(b) Vasomotor
symptom score
improved
compared to
baseline
(secondary
outcome).
Primary outcome
was improved
symptoms of
depression
(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
3
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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).
4
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Medicines Q&As
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
http://cks.nice.org.uk/ on 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. Royal College of Obstetricians and Gynaecologists.
September 2010 Accessed via www.rcog.org.uk on 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):32783283.
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.
5
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Medicines Q&As
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 www.medicines.org.uk
 NICE Clinical Knowledge Summaries. Accessed via http://cks.nice.org.uk/
 NICE Evidence. Accessed via www.evidence.nhs.uk
 British Menopause Society website. Accessed via www.thebms.org.uk
 International Menopause Society website. Accessed via http://www.imsociety.org/
 Royal College of Obstetricians and Gynaecologists website. Accessed via http://www.rcog.org.uk/
 Cochrane database. Accessed via http://www.thecochranelibrary.com/view/0/index.html
6
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