Does menopause really cause depression?

How common are depressive symptoms among perimenopausal and postmenopausal women, and how do depression symptoms differ at various stages in life?

Robert P. Kauffman, MD, MSCP, professor, department of obstetrics and gynecology, and assistant dean for research education, Texas Tech University Health Sciences Center School of Medicine, observes: “There are psychosocial issues for the perimenopausal/menopausal woman that are somewhat unique compared to earlier life. The development of chronic or disabling medical disorders, loss of children from the home (empty nest), caring for their own aging parents, low physical functioning, marital stress, negative attitudes toward menopause (and loss of fertility), presence of vasomotor symptoms, dyspareunia, and sleep disturbance are somewhat age-specific risk factors for developing depressive disorders in the perimenopausal transition.”

Indeed, several studies have found that women are more vulnerable to experiencing depression during this life transition. Investigators of a study titled “Does menopause elevate the risk for developing depression and anxiety? Results from a systematic review,” published in Australasian Psychiatry in March 2023, concluded, “Menopause increases vulnerability to depression and anxiety, perhaps via estrogen fluctuations affecting serotonin and GABA [γ-aminobutyric acid].” The authors also noted that “underlying neuroticism and contemporaneous adverse life events are also risk factors for menopausal decompensation with depression.”¹

Yet as it turns out, a direct connection between menopause and depression has become a bit controversial. Recently, authors of another study, this one in The Lancet, assessed reports showing a link between mental health conditions and the menopause transition, summarized, “We reviewed 12 prospective studies reporting depressive symptoms, major depressive disorder, or both over the menopause transition and found no compelling evidence for a universal increased risk for either condition,” adding, “the increased risk of major depressive disorder over the menopause transition appears predominantly in individuals with previous major depressive disorder.”²

Kauffmann explains: “Women who have a prior diagnosis of a depressive disorder are at higher risk for depression during the menopausal transition than those without such a history. Depression is defined in the perimenopause and menopause by the same definition as used in other age groups and genders, using the DSM-V [Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition)] criteria. The perimenopause is considered a ‘vulnerable’ time for women to develop depression or depressive symptoms, like puberty and pregnancy/postpartum. We know that estrogen does affect production and action of serotonin, dopamine, and norepinephrine in the brain. There is not, however, a direct cause-and-effect relationship between depression and hypoestrogenism. FSH [follicle-stimulating hormone] and estradiol levels do not correlate or predict major depression in the menopausal transition and menopause.”

However, Nishath Ali, MD, FACOG, associate professor, North American Menopause Society certified menopause practitioner, and codirector, The Menopause Center, department of obstetrics and gynecology, Texas Children’s Pavilion for Women, Baylor College of Medicine, contends that there are still “many women who experience depression because of hormonal changes. We see it with PMS/PMDD [premenstrual syndrome/premenstrual dysphoric disorder], postpartum depression, and in perimenopause and menopause. It is much more common than appreciated by the community,” yet she also agrees that “risk factors can include severity of vasomotor symptoms, socioeconomic factors, and health issues such as prior depression.”

To add to these varying voices is a prospective study, published in the Archives of General Psychiatry, of premenopausal women with and without a lifetime history of major depression. In this report, a cohort of these women (aged 36-45 years) with no lifetime diagnosis of major depression were assessed. Noted these study authors, “Premenopausal women with no lifetime history of major depression who entered the perimenopause were twice as likely to develop significant depressive symptoms as women who remained premenopausal, after adjustment for age at study enrollment and history of negative life events.”³

Perhaps an executive statement in the March issue of The Lancet sums it up best: “Menopause is an inevitable life stage for half the world’s population, but experiences vary hugely. Some women have few or no symptoms over the menopause transition while others have severe symptoms that impair their quality of life and may be persistent.”⁴

Symptoms of depression during menopause
In the March issue of Menopause,⁵ a study evaluating the effect of current depressive symptoms on sexual functioning during menopause was published. In the study, the investigators concluded, “Among perimenopausal and postmenopausal women, current depressive symptoms were associated with low sexual function.”

However, low sexual function, as we all know, is only 1 indicator of depression. The authors of an article, “Depression during and after the perimenopause: impact of hormones, genetics, and environmental determinants of disease,” in Obstetrics and Gynecology Clinics of North America, published a table defining major vs minor depressive symptoms that could appear during menopause. Major depressive episodes include 5 or more of the following symptoms most days for at least 2 weeks:⁶

--Depressed mood (eg, sad, hopeless)

--Decreased interest or pleasure

--Weight change (>5% of body weight/month), or change in appetite

--Sleep disturbance

--Feelings of worthlessness or excessive guilt

--Difficulty concentrating

--Psychomotor agitation or slowing

--Recurrent thoughts of death

The authors concluded, “Evaluation for depression and treatment may be conducted in the primary care practice and includes consideration of hormone therapy and antidepressants, alone or in combination, and cognitive behavioral therapy.”

Therapies to treat depression
To treat depressive symptoms in this population, Kauffman suggests: “Treatment should be highly individualized: In perimenopausal and newly menopausal women with bothersome vasomotor symptoms (VMS), hormone replacement therapy (HRT) is appropriate, assuming no contraindication. Moderate to severe VMS can cause considerable quality of life (QOL) issues as well as contribute to sleep disturbance. In a subset of individuals, HRT may be all that is needed. Close monitoring for improvement in depressive symptoms is wise if HRT alone is prescribed. Randomized trials have suggested that HRT alone may not be adequate in many women who meet criteria for major depressive disorders, and these women are candidates for antidepressant therapy and/or counseling. There [are] no data on the NK3 inhibitor fezolinetant (Veozah; Astellas Pharma) and mood although it is approved for VMS, and accordingly might be an option for those who are bothered by VMS and sleep disturbance alone who cannot or will not use HRT.” Friedman also suggests that in “menopausal women who meet criteria for major depressive disorder, antidepressant utilization is supported by clinical trials. Desvenlafaxine (Khedezla; Osmotica Pharma) has good supportive data in randomized trials although all SSRI [selective serotonin reuptake inhibitor] or SNRI [serotonin and norepinephrine reuptake inhibitor] antidepressants may be effective. In women who have been treated successfully in the past with a certain antidepressant, it is reasonable to restart that drug again. SSRI and SNRI are also beneficial for treatment of VMS, although they are generally not as effective as HRT.”

Ali adds: “When depressive symptoms occur with perimenopause and menopause symptoms, estradiol has shown efficacy in improvement of both categories. Effectively managing this phase may require a multidisciplinary, coordinated approach which is individualized to each patient. Menopausal women may have a differing response to therapy with SSRIs vs premenopausal women, but there is more understanding and research needed in this area.”

What can obstetrician-gynecologists (ob-gyns) do proactively to treat depression in this population group?
Kauffman suggests: “Menopausal care is much more than doing a pap smear and mammogram. It is well documented that primary care residency training in the United States is deficient in menopausal medicine education, including ob-gyn training. A complete psychiatric and medical history should be taken at annual visits. The former is important as history of depression is a risk factor for recurrent depression in the climacteric. Women should be asked specifically about VMS and dyspareunia as some women do not voluntarily discuss these issues. Concerns about relationships and growing children should be addressed. Chronic and sometimes disabling medical conditions are risk factors for depression. Often, care for aging relatives presents unique stressors. Some validated form of depression screening can be completed prior to physician encounter and should be addressed during the annual patient encounter. Counseling and cognitive behavioral therapy are evidence-based approaches that may benefit many women alone, particularly those with psychosocial concerns. Physicians should be familiar with the psychopharmacology and guidelines for antidepressant use.”

References
1. Alblooshi S, Taylor M, Gill N. Does menopause elevate the risk for developing depression and anxiety? Results from a systematic review. Australas Psychiatry. 2023;31(2):165-173. doi:10.1177/10398562231165439

2. Brown L, Hunter MS, Chen R, et al. Promoting good mental health over the menopause transition. Lancet. 2024;403(10430):969-983. doi:10.1016/S0140-6736(23)02801-5

3. Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. 2006;63(4)385-390. doi:10.1001/archpsyc.63.4.385

4. Menopause 2024. Lancet. March 5, 2024. Accessed April 4, 2024. https://www.thelancet.com/series/menopause-2024

5. Stevens EB, Wolfman W, Hernandez-Galan L, Shea AK. The association of depressive symptoms and female sexual functioning in the menopause transition: a cross-sectional study. Menopause. 2024;31(3):186-193. doi:10.1097/GME.0000000000002309

6. Bromberger JT, Epperson CN. Depression during and after the perimenopause: impact of hormones, genetics, and environmental determinants of disease. Obstet Gynecol Clin North Am. 2018;45(4):663-679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226029/