Precision medicine of menopause and depression: treating hot flashes with antidepressants

Many women have hot flashes, night sweats, poor sleep and low mood in the years before and after menopause. Menopause is not simply a lack of estrogen: it is a complex transition that affects the body and the mind. Effective treatments include hormone therapy, some antidepressants, gabapentin and newer non-hormonal drugs. Your genes affect how well some of these work and how safe they are for you. This article reviews the main options and how a DNA test can help choose between them.

Is menopause a gradual change?

Menopause is not a slow, gradual transition. A 2026 study in Nature Medicine analyzed about 300 million laboratory tests from two large cohorts and found a sudden, step-like change around the final menstrual period in many body systems, including hormones, bone, liver, kidney and blood fats. Some of these changes began more than a decade before the last period. Such changes were not seen in men, and the drastic menopausal changes were ameliorated in women using hormone replacement therapy. Because the liver and kidneys clear many medications, this is one more reason to review your medications and doses with your health care provider around menopause.

How are menopause, sleep and depression linked?

Hot flashes and night sweats disrupt sleep, and poor sleep together with hormonal changes can affect mood, self-esteem and relationships. The years around menopause are also a time of higher risk for depression, especially in women who have had depression before. Many symptoms improve with lifestyle changes such as regular exercise, a healthy diet and stress reduction, and cognitive behavioural therapy (CBT) can help with both hot flashes and mood. If you feel unable to cope, talk to your health care provider about counselling and medical treatment.

What treatments are available?

The right choice depends on your symptoms, age, time since menopause, personal and family history of breast cancer, blood clots, heart disease and dementia, other medications, and your genes.

Treatment	Helps with	Genes
Hormone therapy (estrogen, with a progestogen if you have a uterus)	Hot flashes, sleep, vaginal dryness, bone loss; may improve mood in perimenopause	F5, F2
Paroxetine, citalopram, escitalopram, sertraline	Depression, anxiety, hot flashes	CYP2D6, CYP2C19, CYP2B6
Venlafaxine, desvenlafaxine	Depression, anxiety, hot flashes	CYP2D6, CYP3A4
Gabapentin	Hot flashes, especially at night; sleep	None
Fezolinetant (Veozah)	Moderate to severe hot flashes	CYP1A2
Elinzanetant (Lynkuet)	Moderate to severe hot flashes	CYP3A4

Is hormone therapy safe?

Hormone therapy is the most effective treatment for hot flashes and also prevents bone loss and fractures. According to the 2022 hormone therapy position statement of The North American Menopause Society and the 2021 Canadian SOGC menopause guideline, for healthy women younger than 60 or within 10 years of menopause, the benefits usually outweigh the risks. Starting later, or after age 60, carries greater risks of heart disease, stroke, blood clots and dementia. The type, dose, route and duration should be chosen with your health care provider and reviewed regularly. Women who still have a uterus need a progestogen with estrogen to protect the lining of the uterus.

In perimenopausal women with depression, a randomized trial found that estradiol skin patches improved depressive symptoms. Hormone therapy is not approved as a treatment for depression, but it may help mood when depression comes with hot flashes in perimenopause.

Blood clots and your genes

Women who carry Factor V Leiden (a variant in the F5 gene) or the prothrombin variant in the F2 gene have a higher risk of blood clots in the legs and lungs. One copy of Factor V Leiden raises the risk several times, and two copies raise it much more. Oral estrogen adds to this risk. In the ESTHER study, oral estrogen increased the risk of blood clots about four-fold, while estrogen patches and gels did not, and micronized progesterone was not linked to clots. Women who carry F5 or F2 variants should avoid oral estrogen and discuss non-hormonal options or skin patches and gels with their health care provider. For more, read Birth control and blood clots.

Hormone therapy and dementia

Low-dose vaginal estrogen treats vaginal dryness and, in a large study of nurses, was not linked to higher risks of heart disease, stroke, cancer or blood clots. For systemic estrogen-only therapy, a Danish registry study of women who had had a hysterectomy found a higher rate of dementia in users, rising with longer use. This was an observational study and cannot prove that estrogen caused dementia, but it is one reason to discuss the length of treatment with your health care provider.

What about "natural" and compounded hormones?

Custom-compounded "bioidentical" hormones are not regulated like approved products, and their dose and purity can vary. Canadian and North American guidelines do not recommend them. Herbal products such as black cohosh have weak evidence for hot flashes, and St. John's wort interacts with many medications. Tell your pharmacist about any natural products you take.

Which antidepressants help with hot flashes and depression?

Antidepressants are a first choice for women with significant depression around menopause, and several also reduce hot flashes. Paroxetine (Paxil), citalopram, escitalopram, venlafaxine and desvenlafaxine have the best evidence for hot flashes. Low-dose paroxetine (7.5 mg) is approved in the United States specifically for hot flashes. Paroxetine is more often linked to weight gain than other SSRIs; read more in SSRIs and weight gain.

Important for women taking tamoxifen: paroxetine and fluoxetine strongly block the CYP2D6 enzyme that activates tamoxifen and may make it less effective. Venlafaxine, desvenlafaxine and, with less certainty, escitalopram and citalopram are preferred. Read more in Can't tolerate tamoxifen side effects?

What are the non-hormonal options for hot flashes?

Gabapentin (Neurontin), an antiepileptic also used for nerve pain, reduces hot flashes and can improve sleep, especially when taken at bedtime. It can cause dizziness and drowsiness.

Fezolinetant (Veozah) and elinzanetant (Lynkuet) are a new class of non-hormonal drugs made specifically for moderate to severe hot flashes. They block neurokinin receptors in the part of the brain that controls body temperature: fezolinetant blocks the NK3 receptor, and elinzanetant blocks both NK1 and NK3. They do not contain hormones, so they are an option for women who cannot or prefer not to use hormone therapy, and they can be used with antidepressants, with some exceptions:

• Fezolinetant is broken down by CYP1A2, the enzyme that also breaks down caffeine. It must not be combined with drugs that block CYP1A2, including the antidepressant fluvoxamine. Smoking speeds up CYP1A2 and lowers fezolinetant levels. Liver blood tests are needed before and during treatment.
• Elinzanetant is broken down by CYP3A4, so drugs that strongly block or speed up this enzyme should be avoided. It can cause sleepiness.

How do your genes affect menopause and depression treatment?

Many antidepressants used around menopause depend on two liver enzymes, CYP2D6 and CYP2C19. Many women are not normal metabolizers for one or both. According to the CPIC 2023 antidepressant guideline:

• Paroxetine (CYP2D6): poor metabolizers should start at a lower dose; ultrarapid metabolizers should consider another drug.
• Venlafaxine (CYP2D6): poor metabolizers should consider another drug, such as desvenlafaxine, which is broken down by CYP3A4.
• Citalopram and escitalopram (CYP2C19): poor metabolizers should start at a lower dose; ultrarapid metabolizers should consider another drug.
• Sertraline (CYP2C19 and CYP2B6): poor metabolizers may need a lower starting dose.

Slow metabolism can raise drug levels and side effects, while very fast metabolism can lower drug levels so the medication helps less. For fezolinetant and elinzanetant there are no genetic dosing guidelines, but knowing your CYP1A2 and CYP3A4 status and your other medications helps a pharmacist avoid interactions. Read more about choosing antidepressants with a DNA test.

Summary

• Hot flashes, poor sleep and depression often occur together around menopause.
• Hormone therapy is the most effective treatment for hot flashes and is usually safe for healthy women under 60 or within 10 years of menopause.
• Women who carry F5 (Factor V Leiden) or F2 variants should avoid oral estrogen and discuss safer options.
• Several antidepressants treat both depression and hot flashes; the choice and dose can be guided by CYP2D6 and CYP2C19 results.
• Women taking tamoxifen should avoid paroxetine and fluoxetine.
• Gabapentin, fezolinetant and elinzanetant are non-hormonal options; fezolinetant must not be combined with fluvoxamine.
• The Pillcheck test includes CYP2D6, CYP2C19, F5, F2 and other genes. A Pillcheck pharmacist reviews your results and medications to help you and your doctor choose the best treatment.

Frequently asked questions

Can antidepressants treat hot flashes?

Yes. Paroxetine, citalopram, escitalopram, venlafaxine and desvenlafaxine reduce hot flashes, even in women without depression, although less than hormone therapy.

Is hormone therapy safe if I carry Factor V Leiden?

Oral estrogen raises the risk of blood clots, especially in women with Factor V Leiden or the F2 prothrombin variant, and should be avoided. Discuss non-hormonal options or estrogen patches and gels with your health care provider.

Which antidepressants should I avoid if I take tamoxifen?

Paroxetine and fluoxetine, because they block CYP2D6, the enzyme that activates tamoxifen. Venlafaxine and desvenlafaxine are usually preferred.

What is fezolinetant (Veozah)?

A non-hormonal pill for moderate to severe hot flashes. It needs liver blood tests and must not be taken with fluvoxamine or other drugs that block CYP1A2.

Can a DNA test help choose a menopause treatment?

Yes. It shows how you metabolize many antidepressants and whether you carry clotting variants that make oral estrogen riskier.

References

The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794.

Yuksel N, Evaniuk D, Huang L, et al. Guideline No. 422a: Menopause: Vasomotor Symptoms, Prescription Therapeutic Agents, Complementary and Alternative Medicine, Nutrition, and Lifestyle. J Obstet Gynaecol Can. 2021;43(10):1188-1204.

Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68.

Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115(7):840-845.

Pourhadi N, Mørch LS, Holm EA, et al. Dementia in Women Using Estrogen-Only Therapy. JAMA. 2024;331(2):160-162.

de Novaes Soares C, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58(6):529-534.

Pridham G, Hayut Y, Lavi-Shoseyov N, et al. Population-scale reconstruction of menopause dynamics reveals a physiological cliff at the final menstrual period. Nat Med. 2026;32(10):3823-3831.

Kaunitz AM, Manson JE. Management of menopausal symptoms. Obstet Gynecol. 2015;126(4):859-876.

Gialeraki A, et al. Oral Contraceptives and HRT Risk of Thrombosis. Clin Appl Thromb Hemost. 2018;24(2):217-225.

Bhupathiraju SN, et al. Vaginal estrogen use and chronic disease risk in the Nurses' Health Study. Menopause. 2019;26(6):603-610.

Thurston RC, Huang AJ. The Swinging Pendulum of Menopausal Hormone Therapy. JAMA Intern Med. 2025. doi:10.1001/jamainternmed.2025.5340.

U.S. Food and Drug Administration. Menopause: Medicines to Help You.