Which is better for control of postmenopausal symptoms, paroxetine (Paxil) or fluoxetine (Prozac) or venlafaxine (Effexor)?

Venlafaxine is Superior for Postmenopausal Vasomotor Symptoms

Venlafaxine 75 mg daily is the preferred first-line nonhormonal treatment for postmenopausal hot flashes, demonstrating superior efficacy (61% reduction in hot flash scores) compared to paroxetine and fluoxetine. 1, 2

Evidence-Based Ranking

First Choice: Venlafaxine

• Venlafaxine at 75 mg/day reduces hot flash scores by 61% compared to 27% with placebo, with dose-dependent efficacy starting at 37.5 mg/day (37% reduction) and maximizing at 75-150 mg/day 3, 4
• The American College of Obstetricians and Gynecologists recommends starting at 37.5 mg daily and increasing to 75 mg after 1 week if symptoms persist 1
• Venlafaxine demonstrates faster onset of action (within 1 week) compared to SSRIs 2
• This SNRI simultaneously addresses hot flashes, depression, and anxiety, making it ideal for women with multiple menopausal symptoms 1
• Side effects are dose-related (dry mouth, decreased appetite, nausea, constipation) but the 75 mg dose provides optimal balance of efficacy and tolerability 3

Second Choice: Paroxetine

• Paroxetine 7.5 mg daily reduces hot flash composite scores by 62-65% in controlled trials 3, 5
• The National Comprehensive Cancer Network recommends paroxetine 7.5 mg as an alternative first-line option that significantly reduces both frequency and severity of vasomotor symptoms 3, 1
• Critical caveat: Paroxetine must be avoided in women taking tamoxifen due to strong CYP2D6 inhibition that blocks tamoxifen conversion to active metabolites 3, 2
• Lower doses (7.5 mg) are effective for vasomotor symptoms compared to antidepressant doses (20-60 mg/day) 5

Third Choice: Fluoxetine (Not Recommended)

• Fluoxetine shows the weakest and most inconsistent efficacy, with only 50% reduction in hot flash scores versus 36% for placebo 3
• Marked variability in response: only 42% of women improve by >50%, while 27% experience worsening hot flashes 3
• Long-term efficacy is not demonstrated—at 9 months, fluoxetine was no better than placebo 3, 6
• A 2007 systematic review concluded that current evidence does not support the use of fluoxetine for menopausal vasomotor symptoms 7
• Fluoxetine should also be avoided in women taking tamoxifen due to CYP2D6 inhibition 2

Clinical Algorithm

Step 1: Assess tamoxifen use

• If on tamoxifen → Choose venlafaxine (paroxetine and fluoxetine are contraindicated) 3, 2
• If not on tamoxifen → Proceed to Step 2

Step 2: Evaluate comorbid symptoms

• If depression, anxiety, or insomnia present → Venlafaxine 37.5-75 mg daily 1, 8
• If isolated hot flashes only → Venlafaxine 75 mg daily or paroxetine 7.5 mg daily 1, 2

Step 3: Initiate treatment

• Venlafaxine: Start 37.5 mg daily, increase to 75 mg after 1 week 1
• Paroxetine: Start 7.5 mg daily (no titration needed) 3
• Assess response at 2-4 weeks 2

Step 4: Discontinuation

• Both venlafaxine and paroxetine require gradual tapering to prevent withdrawal symptoms (anxiety, dizziness, nausea) due to their short half-lives 3, 2

Common Pitfalls to Avoid

• Never use paroxetine or fluoxetine in women on tamoxifen—this is the most critical drug interaction to avoid 3, 2
• Never abruptly discontinue venlafaxine or paroxetine—always taper gradually over 1-2 weeks 3
• Do not use fluoxetine as first-line therapy—the evidence shows inconsistent efficacy and lack of long-term benefit 3, 6, 7
• Do not use antidepressant doses for vasomotor symptoms—much lower doses are effective (venlafaxine 75 mg vs 150-225 mg for depression; paroxetine 7.5 mg vs 20-60 mg for depression) 3, 5

Alternative Considerations

If venlafaxine and paroxetine fail or are not tolerated, gabapentin 900 mg/day at bedtime reduces hot flash severity by 46% and may be particularly useful for women with sleep disturbance 3, 1, 2