What are the recommended antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), for managing mood swings and hot flashes in menopause?

Antidepressants for Menopausal Mood Swings and Hot Flashes

For moderate to severe hot flashes and mood symptoms in menopause, start with venlafaxine 37.5 mg daily, increasing to 75 mg daily after one week, or paroxetine 10 mg daily, increasing to 20 mg daily after one week if needed—but avoid paroxetine and fluoxetine entirely in women taking tamoxifen due to drug interactions that reduce tamoxifen efficacy. 1

First-Line Antidepressant Options

SNRI: Venlafaxine (Preferred for Most Patients)

• Venlafaxine demonstrates superior efficacy with a 61% reduction in hot flash scores at 75 mg daily versus 27% with placebo, making it the most effective SSRI/SNRI option 1
• Start at 37.5 mg daily and increase to 75 mg daily after one week, as this is the optimal dose balancing efficacy and tolerability 1
• Venlafaxine has minimal CYP2D6 inhibition, making it safe for women on tamoxifen 2
• Rapid onset of action occurs within 1 week, with benefits on quality of life demonstrated over 12 weeks 1
• Common side effects include dry mouth, decreased appetite, nausea, and constipation, but these are dose-related 1
• Must be tapered gradually on discontinuation to prevent withdrawal symptoms 1

SSRI: Paroxetine (Alternative First-Line)

• Controlled-release paroxetine reduces hot flash composite scores by 62% at 12.5 mg daily and 65% at 25 mg daily 1
• For standard formulations, start at 10 mg daily, increasing to 20 mg daily after one week if symptoms persist 1
• Critical contraindication: Paroxetine is a potent CYP2D6 inhibitor and should NOT be used in women taking tamoxifen, as it blocks conversion of tamoxifen to its active metabolite endoxifen 1, 3
• Side effects include nausea, fatigue, dizziness, headache, dry mouth, and sexual dysfunction, typically mild and transient 3
• Requires gradual tapering on discontinuation due to withdrawal risk 1, 3

Second-Line SSRI Options

Sertraline

• Sertraline 50 mg daily is superior to placebo in reducing hot flashes, particularly in tamoxifen users 2
• Weak or no CYP2D6 effects make it preferable to paroxetine or fluoxetine in breast cancer patients on tamoxifen 2
• Mixed results in general populations with substantial individual variability in response 1, 2
• Does not improve quality of life measures despite reducing hot flash frequency 1
• Must be tapered gradually to prevent discontinuation symptoms 2

Citalopram

• May be effective in patients who do not respond to venlafaxine 1
• Minimal CYP2D6 effects, making it safer for tamoxifen users 1, 2
• Long-term efficacy not demonstrated—one study showed no superiority over placebo at 9 months 1

Fluoxetine

• Decreased hot flash composite score by 50% versus 36% for placebo 1
• Marked variability in response: 42% improve by >50%, 30% improve by <50%, and 27% experience worse hot flashes 1
• Potent CYP2D6 inhibitor—avoid in tamoxifen users 1

Treatment Algorithm

Step 1: Initial Assessment

• Determine if patient is taking tamoxifen or other medications metabolized by CYP2D6 1
• Screen for contraindications: monoamine oxidase inhibitor use, bipolar disorder (risk of inducing mania) 1
• Assess for concurrent depression (favors SSRI/SNRI) or neuropathic pain (favors gabapentin) 1

Step 2: First-Line Treatment Selection

• If NOT on tamoxifen: Choose venlafaxine 37.5 mg daily (increase to 75 mg after 1 week) OR paroxetine 10 mg daily (increase to 20 mg after 1 week if needed) 1
• If on tamoxifen: Use venlafaxine, sertraline 50 mg daily, or citalopram—never paroxetine or fluoxetine 1, 2, 3

Step 3: Response Assessment

• Evaluate response at 4 weeks—if no improvement by then, treatment is unlikely to be effective 1
• If venlafaxine fails, try paroxetine (if not on tamoxifen), and vice versa 1
• Consider switching to sertraline or citalopram as second-line options 2

Step 4: Alternative if SSRIs/SNRIs Fail

• Consider gabapentin as an alternative (no CYP2D6 interactions, no sexual dysfunction, no withdrawal syndrome) 1
• Fezolinetant is emerging as a preferred non-hormonal option with fewer side effects and no tamoxifen interactions 4

Critical Pitfalls to Avoid

Drug Interactions with Tamoxifen

• Paroxetine and fluoxetine are potent CYP2D6 inhibitors that block tamoxifen conversion to endoxifen, potentially reducing breast cancer treatment efficacy 1, 3
• The American Society of Clinical Oncology explicitly recommends against paroxetine in women on tamoxifen 3
• Safe alternatives include venlafaxine, desvenlafaxine, sertraline, and citalopram 1, 2

Discontinuation Syndrome

• Short-acting agents (paroxetine and venlafaxine) require gradual tapering to prevent withdrawal symptoms including dizziness, nausea, and mood changes 1
• Never stop these medications abruptly 1

Bipolar Disorder Risk

• SSRIs and SNRIs can induce mania in women with bipolar disorder—use cautiously or avoid 1

Variable Response

• Approximately 10-20% of patients discontinue treatment due to side effects 1, 5
• Some women (up to 27% with fluoxetine) experience worsening hot flashes 1
• Individual trial periods are necessary to assess response given substantial variability 2

Efficacy Compared to Other Options

• Antidepressants are modestly effective compared to estrogen, though no head-to-head studies exist 1
• Venlafaxine 75 mg shows 61% reduction versus gabapentin 900 mg showing 46% reduction in hot flash severity 2
• SSRIs/SNRIs demonstrate good efficacy for concurrent depression, unlike gabapentin or clonidine 1
• Duration of action: SSRIs/SNRIs effective up to 6 weeks, gabapentin up to 12 weeks, clonidine up to 8 weeks 1

Mood Symptoms Consideration

• SSRIs and SNRIs provide dual benefit for both vasomotor symptoms and mood disturbances common in menopause 1, 6, 7
• The mechanism for hot flash reduction appears independent and more rapid than the antidepressant effect 3
• Improvements in sleep, mental health, and vitality may accompany hot flash reduction 5