SSRIs and SNRIs for hot flashes

Several antidepressants reduce hot flashes at low doses, whether or not you are depressed. The benefit is real but modest: roughly one to two fewer hot flashes a day than placebo, with onset within two weeks. The Menopause Society gives SSRIs and SNRIs a Level I recommendation, and one of them, paroxetine 7.5 mg, is FDA-approved specifically for this use.

What they are and how they work

SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors) raise the availability of serotonin, and for SNRIs also norepinephrine, at nerve synapses. Both neurotransmitters influence the hypothalamic temperature control center that misfires during menopause. The exact mechanism for hot flashes is not fully worked out, but the effect appears quickly and at doses lower than those used for depression, which suggests it is separate from the antidepressant effect.

The drugs with positive large trials are paroxetine, escitalopram, citalopram, venlafaxine, and desvenlafaxine. Duloxetine has smaller supportive studies. Sertraline and fluoxetine showed only non-significant trends and are not recommended.

What the evidence shows

Paroxetine 7.5 mg (Brisdelle). Two phase 3 trials enrolled 1,174 postmenopausal women with at least 7 to 8 moderate to severe hot flashes a day. In the 12-week study (606 women), the median daily frequency fell by 5.9 with paroxetine versus 5.0 with placebo at week 12, a difference of 0.9. In the 24-week study (568 women), it fell by 5.6 versus 3.9, a difference of 1.7. Severity improved significantly in the 24-week study at both time points but only at week 4 in the 12-week study. The FDA approved it in 2013 on this basis.

Escitalopram 10 to 20 mg. In an 8-week trial of 205 women (nearly half African American), hot flashes fell by 4.6 a day with escitalopram versus 3.2 with placebo, a difference of 1.4. Fifty-five percent of women on escitalopram had at least a 50% reduction, compared with 36% on placebo.

Venlafaxine 75 mg. The MsFLASH trial randomized 339 women to venlafaxine extended-release 75 mg, low-dose oral estradiol 0.5 mg, or placebo for 8 weeks. Frequency fell 47.6% with venlafaxine, 52.9% with estradiol, and 28.6% with placebo. Venlafaxine beat placebo by 1.8 flashes a day; estradiol beat venlafaxine by 0.6 a day, a difference that did not reach significance. Treatment satisfaction was 51% for venlafaxine, 70% for estradiol, and 38% for placebo.

Pooled data. A meta-analysis of 11 SSRI trials in 2,069 women found a reduction of 0.93 hot flashes a day versus placebo and a small-to-moderate improvement in severity; escitalopram ranked highest. The 2023 position statement summarizes the range across SSRI and SNRI trials as 25% to 69% reduction in hot flashes.

How to read this: the evidence that these drugs work is strong and consistent, but the size of the effect is mild to moderate. Placebo response in these trials is substantial, and the drug adds roughly one to two flashes a day on top of it. They do not match the effect size of hormone therapy when hormone doses are optimized.

Doses, how they are taken, time to effect

Suggested dosing from the 2023 position statement:

Drug	Dose range	How to start
Paroxetine mesylate (Brisdelle)	7.5 mg at bedtime	No titration
Paroxetine	10 to 25 mg/day	Start 10 mg
Citalopram	10 to 20 mg/day	Start 10 mg
Escitalopram	10 to 20 mg/day	Start 10 mg (5 mg if sensitive, though 5 mg is untested for efficacy)
Venlafaxine XR	37.5 to 150 mg/day	Start 37.5 mg
Desvenlafaxine	100 to 150 mg/day	Start 25 to 50 mg and titrate

Onset of action is typically within two weeks. Trials measure effect at weeks 4 to 12. Nausea and dizziness, when they occur, usually fade after one to two weeks. In the Brisdelle trials, nausea appeared mostly in the first 4 weeks and fatigue in the first week.

Side effects and who should avoid them

In the pooled Brisdelle trials, the side effects more common than placebo were headache (6.3% vs 4.8%), fatigue (4.9% vs 2.8%), and nausea or vomiting (4.3% vs 2.3%). At venlafaxine doses of 75 and 150 mg, dry mouth, decreased appetite, nausea, and constipation were significantly more common than placebo in a trial in breast cancer survivors. The position statement notes paroxetine 7.5 mg did not cause weight gain or reduced libido in its trials.

Warnings. All antidepressants carry a boxed warning about suicidal thoughts and behaviors in children, adolescents, and young adults. The Brisdelle trials excluded women with a history of suicidal ideation, and one serious case of suicidal ideation and one suicide attempt occurred in the paroxetine arm versus none on placebo. Report any mood change promptly.

Contraindications. Do not combine with a monoamine oxidase inhibitor (or within 14 days of one), and avoid paroxetine with thioridazine or pimozide. Use caution with other serotonergic drugs (risk of serotonin syndrome), uncontrolled seizures, bipolar disorder, low sodium, poorly controlled high blood pressure, and liver or kidney disease. The paroxetine 7.5 mg label also warns about abnormal bleeding, especially with blood thinners or NSAIDs.

Tamoxifen. Paroxetine and fluoxetine strongly inhibit CYP2D6, the enzyme that converts tamoxifen to its active metabolite endoxifen. The Brisdelle label flags this, and the position statement names venlafaxine, desvenlafaxine, escitalopram, and citalopram as safer choices for women on tamoxifen.

Cost and insurance in the US

Paroxetine, citalopram, escitalopram, venlafaxine, and desvenlafaxine are all available as generics. Because hot flashes are an off-label use for these, check your plan’s formulary and copay. Brisdelle (paroxetine 7.5 mg) is a brand product. Insurers may not cover a brand low-dose product when generic 10 mg paroxetine exists, so ask about the price difference before filling.

How they compare with other options

Option	Effect vs placebo	Best fit	Main drawbacks
SSRIs/SNRIs	About 1 to 2 fewer flashes/day	Hot flashes plus low mood or anxiety; women avoiding hormones	Nausea, headache, fatigue, discontinuation symptoms
Gabapentin	Roughly 35 to 38% greater score reduction in pooled trials	Night sweats, sleep disruption	Drowsiness, dizziness
Fezolinetant	About 2.5 fewer flashes/day	Targeted drug, no mood effects	Liver tests, cost
Low-dose estradiol	About 2.3 fewer flashes/day	Women eligible for hormones	Hormone contraindications
CBT	Reduces bother and sleep disruption	Anyone, no drug interactions	Time, access

Questions for your clinician

• Given my mood, sleep, and other symptoms, is an SSRI or SNRI the right first choice?
• Do I take tamoxifen or anything else metabolized by CYP2D6?
• Which specific drug and starting dose, and when do we reassess?
• How do we taper if I want to stop?
• Would generic paroxetine 10 mg be reasonable instead of Brisdelle, and what does each cost on my plan?

If your current clinician is not comfortable with off-label prescribing for menopause, how to find a menopause specialist explains what to look for.