Many women experience unpleasant symptoms leading up to, during, and after menopause. It is not uncommon to have hot flashes, insomnia and depression. Hot flashes can cause substantial physical and psychological discomfort. There are medical treatments available for women experiencing severe symptoms, including hormone therapy, antidepressants, and even antiepileptic drugs. Here we describe some of the treatment options and how DNA tests can help guide medication selection to improve the management of menopause and depression.

Sleep, hormones and mood

It is not always obvious to see the link between menopause and the symptoms of depression. However, sleep deprivation caused by hot flashes and hormonal imbalance can directly impact mood, self-esteem, and interpersonal relationships. Many of these issues can be managed with a lifestyle changes, such as healthy diet, exercise, and stress reduction. However, if you feel unable to cope, psychological counselling and medical treatment may be helpful.

Medications for menopause and depression

When considering medical treatments, it’s important to know that your genetic drug metabolism strongly influences your response to medications. A family history of cancer and heart disease, age, liver and kidney function, the severity of mental health symptoms, and women’s DNA should be taken into consideration to select optimal medications and supplements.

Naturopathy

Although naturopathic remedies are popular, they should be used with caution. Naturopathic compounds contain estrogens that can elevate the risk of endometrial and breast cancers, stroke and heart disease.

Antiepileptics

Gabapentin, also known as Neurontin, is an antiepileptic medication that is also used to treat nerve pain and restless leg syndrome. Gabapentin can reduce hot flashes and improve sleep quality.

Antidepressants

Antidepressants are the first-line treatment for perimenopausal women who experience significant depressive symptoms. Paroxetine (Paxil) is an antidepressant approved for the treatment of depression and, at low dosage, helps reduce hot flashes and other menopause-related symptoms.

For women experiencing insomnia, anxiety and low mood, higher dose paroxetine can be used to manage menopause and depression.

Other types of antidepressants, such as SSRIs (escitalopram, citalopram) and SNRIs (venlafaxine, desvenlafaxine), have also been shown to improve symptoms of menopause and depression. Women with concerns about weight gain may prefer escitalopram.

The role of genetics in drug metabolism

Paroxetine and venlafaxine are metabolized by the CYP2D6 liver enzyme. Escitalopram and citalopram are metabolized by a different liver enzyme called CYP2C19. Genetic variations in both genes can significantly affect the speed of medication metabolism, effectiveness and tolerability. A slow metabolism can dramatically increase the risk of side effects. Whereas a rapid metabolism clears medication too fast, resulting in lower antidepressant levels in the blood. For this reason, rapid metabolizers do not experience remission of menopause and depression symptoms.

Less than 35% of North American women are normal metabolizers (see the green figure above) for both CYP2D6 and CYP2C19 enzymes. Over 18% of women in Canada are rapid metabolizers (see the yellow figure above). It helps to know your genetic profile and how it affects your drug-metabolism for different medication options. The majority of women will benefit from a pharmacogenetic test such as Pillcheck, to help select appropriate menopause and depression treatment.

Hormone replacement for menopause and depression

Clinical studies in perimenopausal women that had depressive symptoms but did not quite meet the criteria for major depression showed that estradiol (estrogen) supplementation significantly improved menopause and depression. The estrogen-treated women had improved depression scores even up to 12 weeks after stopping estrogen compared to the control group.

Estrogen and progesterone are approved for the relief of hot flashes and vaginal atrophy.

Women who receive estrogen or combined hormonal therapy have a lower risk of fractures but a higher risk of blood clots, gallbladder disease and urinary incontinence. Women that carry genetic variations in the F5 gene (also known as the Factor V Leiden) and the F2 gene that encodes blood clotting factors should avoid using estrogen and progesterone. Factor V Leiden is a common inherited risk factor for deep vein thrombosis (blood clots). These mutations increase the risk of thrombosis by 10-fold in carriers of a single mutation of the F2 gene, and by 100-fold in women with two mutations. by 100-fold in women with two mutations.

Low doses of vaginal estrogen are beneficial to treat vaginal atrophy. However, the use of estrogen-only formulations has been associated with increased dementia. A Danish study of women with hysterectomy identified that Estrogen-only therapy increased dementia rate by over 55% for women who were treated for five years. The risk was even higher (62%) with longer treatment duration. Oral estradiol had a higher risk (increased by 62%) than transdermal formulations (39% increase). Furthermore, estrogen-only therapy specifically increased the risk of Alzheimer’s disease by 79%. Therefore, women with a family history of dementia should consider alternative, non-hormonal therapy options.

Oral hormone replacement therapy is useful for osteoporosis prevention; it should only be considered for women at significant risk of the disease. Oral hormonal treatment should be used at the lowest doses for the shortest duration, even in women known not to have F5 of F2 variants. Pillcheck DNA tests can also assess the risk of thrombosis and the safety of hormone replacement therapy.

Summary

• Antidepressants can help to minimize menopause symptoms including hot flashes and depression
• Selection of antidepressants should be guided by a DNA test of the key liver enzymes CYP2D6 and CYP2C19should be guided by a DNA test of the key liver enzymes CYP2D6 and CYP2C19
• Estradiol in combination with antidepressants can help to reduce menopause and depression symptoms
• Use of naturopathic medicines containing estradiol and formulated estrogen should be limited to women at higher risk of osteoporosis
• Estradiol should not be used by women who carry variations in the F5 or F2 genes that are known to increase the risk of excessive blood clotting
• Pillcheck test includes variations of CYP2D6, CYP2C19, F5, F2 and other genes. Pillcheck results can help you, and your doctor evaluate treatment options and select the optimal medications to treat menopause and depression symptoms

References

Kaunitz AM and Manson JE Management of menopausal symptoms. Obstetrics and gynecology (2015) 126(4), 859.

Robakis T et al. Hormonal contraceptives and mood: review of the literature and implications for future research. Current psychiatry reports (2019).  21(7), 57.

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. Archives of general psychiatry (2001) 58(6), 529-534.

Genant  HK et al., Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Archives of internal medicine (1997) 157(22), 2609-2615.

The 2017 hormone therapy position statement of The North American Menopause Society Menopause: The Journal of The North American Menopause Society Vol. 24, No. 7, pp. 728-753.

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

Bhupathiraju SN et al., Vaginal estrogen use and chronic disease risk in the Nurses’ Health Study. Menopause. 2018 Dec 17;26(6):603-610. doi: 10.1097/GME.0000000000001284.

Pourhadi N et al., Dementia in Women Using Estrogen-Only Therapy. JAMA. Published online December 18, 2023. doi:10.1001/jama.2023.23784.