Journal reference: 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): 267-74 ^[1]

Link: http://dx.doi.org/10.1001/jama.2010.2016

Published: 19 January 2011

Evidence cookie says...

Escitalopram (Lexapro) is probably associated with a mild improvement in the frequency and severity of hot flushes in peri-menopausal women. Up to 70% of the improvement in hot flushes can be attributed to non-drug mediated effects. Escitalopram like other SSRI is a valid non-hormonal therapeutic option for hot flushes though with limited efficacy. This study is subject to possible funding bias. Note: escitalopram is not PBS listed or TGA approved for this indication; prescribers must provide a private prescription and inform patients that it is being used “off-label”.

More details:

Article details

Study design:

multicentre, double-blind randomised controlled trial

Study aim:

to determine the efficacy and tolerability of escitalopram in alleviating the symptoms of menopausal hot flashes (flushes)

Methods summary:

• multisite study
• placebo-controlled, double-blind randomised design
• enrollment stratified by self-reported race
  • African American
  • white
  • other
• randomised to either placebo treatment or escitalopram (Lexapro) 10 mg daily
  • escitalopram was increased to 20 mg daily (or increase in the matched placebo) after 4 weeks of treatment if hot flash frequency did not reduce by 50% or a decrease in hot flash severity

Recruitment:

• July 2009 to June 2010
• mass mailings to age eligible women using purchased mailing lists and health-plan enrollment files

Eligible women:

• aged 40-62 years with:
  • menopause transition (amenorrhoea ≥ 60 days in the past year)
  • or postmenopausal (≥ 12 months since last menstrual period or bilateral oophorectomy)
  • or hysterectomy with FSH > 20 mIU/mL and oestradiol ≤ 50 pg/mL
• general good health as determined by medical history, a brief physical examination and standard blood tests
• at least 28 hot flashes or night sweats per week (recorded on daily diaries for 3 weeks)
• hot flashes or night sweats rated as bothersome or severe on 4 or more days per week
• the frequency in week 3 did not decrease by more than 50% from the mean weekly levels in weeks 1 and 2

Exclusion criteria:

• use in the past 2 months of:
  • psychotropic medications
  • prescription, over-the-counter, or herbal therapies for hot flashes in the past 30 days
  • hormone therapy
  • hormonal contraceptives
  • selective oestrogen receptor modulators
  • aromatase inhibitors
• current severe medical illness
• major depressive episode
• drug or alcohol abuse in the past year
• suicide attempt in the past 3 years
• lifetime diagnosis of bipolar disorder or psychosis
• uncontrolled hypertension
• history of endometrial or ovarian cancer
• myocardial infarction
• angina or cerebrovascular events

Randomisation:

• by a secure Web-based database
• computerised inventory system for dispensing identical-appearing pills in bottles with unique identifiers
• participants and study site personnel were blinded to treatment assignments until all data were collected and entered in the computer database

Primary outcome:

• 7-day mean of hot flash frequency at weeks 4 and 8
  • total number of hot flashes or night sweats in a 24-hour period
• 7-day mean of hot flash severity at weeks 4 and 8
  • severity rated from 1 to 3 (mild, moderate, severe)

Secondary outcomes:

• hot flash bother
  • rated from 1 to 4 (none, a little, moderately, a lot)
  • “clinical improvement” (decrease of ≥ 50% in the frequency of hot flashes or night sweats at 8 weeks as compared to baseline)

Analyses:

• possible correlates assessed using self-report questionnaires completed a baseline and weeks 4 and 8:
  • menopause status (transition, post-menopausal)
  • self-reported health on a 5-point scale
  • depressed mood as assessed by Patient Health Questionnaire domains of depression (PHQ-9)
  • anxiety as assessed by Generalized Anxiety Disorder (GAD-7)
  • smoking status
  • alcohol use
  • body mass index
  • demographic variables
• adverse events assessed at each visit using a self-administered questionnaire
• apparent a priori power calculation
  • 90 women in each treatment group
  • 90% power to detect a 52% difference in frequency between groups
  • 90% power to detect an effect size of 0.52 standard deviation units for severity between groups
  • 80% power to detect a difference of 3 hot flashes per day with escitalopram by race
• intention to treat analysis (though limited to those who provided diary data; 98% of those randomised)

Results summary:

Primary outcome:

• hot flash frequency, adjusted for race, site, baseline frequency, mean (SD):
  • baseline: 9.78 (5.60) per day
  • escitalopram group (week 8): 5.26 (95% CI 4.08-6.43) per day
  • placebo group (week 8): 6.43 (95% CI 5.12-7.73) per day
  • difference (week 8): -1.41 (95% CI -2.69 to -0.13), P < 0.001
  • note: there is no statistically signficant difference between the two groups as the 95% confidence intervals overlap
• hot flash severity, adjusted for race, site, baseline severity, three point scale (1-3)
  • baseline: 2.17 (0.45)
  • escitalopram group (week 8): 1.63 (95% CI 1.51-1.76)
  • placebo group (week 8): 1.89 (95% CI, 1.77-2.02)
  • difference (week 8): -0.22 (95% CI -0.40 to -0.05), P < 0.001
  • note: the result is just statistically significant (the confidence intervals almost overlap)

Secondary outcomes:

• clinical improvement at week 8 (≥ 50%  reduction from baseline in hot flash frequency)
  • escitalopram vs placebo: 55% vs 36%, P = 0.009

Dose:

• mean dose of escitalopram at week 8 was 15.4 mg
• 87% of participants were adherent to their study dose (at least 70% of dispensed pills)

Adverse events:

• newly emergent adverse events were reported by 53% in the escitalopram group and 63% in the placebo group, P = 0.20
• 7 stopped treatment in the escitalopram group due to adverse events
• 2 stopped treatment in the placebo group due to adverse events, P = 0.17

Study conclusion:

Among healthy women, the use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up.

Participants:

• July 2009 to June 2010
• mass mailings to age eligible women using purchased mailing lists and health-plan enrollment files
• 3107 assessed for eligibility by telephone → 557 completed eligibility form
  • 352 excluded
    • 237 did not meet inclusion criteria
    • 93 withdrew
    • 22 other reasons
• 205 women randomised
• mean age: 53.9 years
• approximately half the participants were white and half African American
• approximately half had never smoked

Methodological weaknesses

• the major limitation in this study is the lack of statistical power
  • the methodological assumption that the difference in hot flash frequency between escitalopram and placebo groups would be of the magnitude 52% on hindsight seems unrealistically optimistic
  • the resultant low number of study participants limits much of the analysis
  • lack of statistical difference in subgroup analyses may not be meaningful
• positivist reporting of results favouring escitalopram:
  • despite the explicit statement by the study authors that escitalopram was “associated with a significant reduction in the frequency of hot flashes relative to placebo” (p. 270) ^[1], there was in fact no statistically significant difference between the two groups for this primary outcome (there is substantial crossover of the 95% confidence intervals)
  • the difference between groups favouring escitalopram in reducing hot flash severity is only just statistically significant; with the real effect difference conceivably being a clinically irrelevant 0.05 on the three point scale from 1-3
• results for adverse events are of limited utility:
  • over 60% of the placebo group reported any “adverse event”
  • it is likely that the self-reported questionnaire for adverse events lacks construct validity; that is, it is not accurately measuring the true rate of adverse events
  • there were too few participants who stopped treatment due to adverse events (7 in the escitalopram group and 2 in the placebo group) for the analysis to be meaningful
• limitation of placebo control:
  • patients on escitalopram were significantly more likely to be aware (correctly guessed which study group there were in: 59% vs 40%) that they were on active treatment
  • this may lead to an expectancy bias (Rosenthal effect) favouring the escitalopram group

Methodological strengths

• thorough blinding of participants and researchers throughout the trial
• rigorous randomisation procedure
• ethnically diverse participants (though few ethnicities apart from white Caucasians and African American)
• attempted to measure and adjust for psychological confounding factors (depression and anxiety)

Biases and conflicts of interests

• Freeman EW (lead author) received research support and honoria from Forest Laboratories (the developer of Lexapro) and a number of other pharmaceutical companies
• Cohen LS (fifth author) received honoria from Forest Laboraties, and honoria and research support from a number of other pharmaceutical companies
• Joffe (sixth author) received research support and honoria from Forest Laboratories and a number of other pharmaceutical companies
• Escitalopram and matching placebo pills were provided by Forest Research Institute

Clinical relevance to primary health care

Selective serotonin reuptake inhibitors (SSRI) have been used for peri-menopausal vasomotor symptoms such as hot flushes (“flashes” in this study) and night sweats. There is some evidence for their efficacy and they offer women an alternative to hormonal therapies.

This study on escitalopram (Lexapro) suffers from being underpowered. The reporting of results and conclusion are biased favouring escitalopram. It should be noted that the study authors and the trial received support from Forest Laboratories, the developer and manufacturer of Lexapro.

The results suggest a small benefit of escitalopram over placebo, 1.41 hot flushes less per day at eight weeks though this was not statistically significant. Almost 70% of the associated reduction in the frequency of hot flushes could be accounted for by non-drug mediated effects. Escitalopram was associated with less severe hot flushes than placebo.

Allowing for the limitations of the study, a reasonable interpretation is that escitalopram:

• possibly/probably associated with a mild improvement in the frequency of hot flushes
• probably associated with a mild to modest improvement  in the severity of hot flushes
• seems to have an effect on peri-menopausal symptoms similar to that of other SSRIs

Escitalopram, like other SSRIs, is a valid therapeutic option for the management of peri-menopausal hot flushes in Australian general practice. General practitioners should be mindful that its overall benefit is likely to be mild. Moreover, improvement in the placebo groups of intervention studies of hot flushes tend to be substantial.

Note: escitalopram is not PBS listed or TGA approved for the treatment of hot flushes or any peri-menopausal symptoms; prescribers must provide a private prescription for this indication and inform patients that it is being used “off-label”.

References

1. 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): 267-74