Depressive symptoms are common during perimenopause. Women with a family or personal history of depression, as well as those with a history of adverse mood changes associated with hormonal fluctuations, such by way of premenstrual syndrome or premenstrual dysphoric disorder, are at increased risk. First-line actions include selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), but menopausal hormone therapy (MHT) may also be an option.
While vasomotor symptoms (VMS) are recognised as an unpleasant aspect of menopause, negative mood changes are also common. Fluctuations in Estrogen and progesterone levels throughout perimenopause can put some women at risk, and their symptoms may present differently than in premenopausal women.
Mood changes can negatively affect a woman’s quality of life. Still, research in this area is limited due to the difficulty in defining both perimenopause and depression, as well as inconsistencies in the assessment tools used This article reviews the effects of Estrogen and progesterone on mood, identifies issues that may put perimenopausal women at risk of developing depressive symptoms, and discusses assessment methods and pharmacological treatment options using selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and/or hormone replacement therapy (HRT). Healthcare professionals who care for perimenopausal women have the opportunity to improve the menopausal transition by addressing negative mood changes.
Belongings of Estrogen and Progesterone on the Brain
Estrogen receptors are found in various areas of the brain that regulate mood, sleep, and cognitive function. Estrogen exerts a beneficial effect on mood by increasing serotonin and norepinephrine levels. This is achieved by limiting monoamine oxidase activity and increasing tryptophan hydroxylase activity, thereby promoting serotonin synthesis and increasing its availability in the synaptic cleft for signalling. In addition, Estrogen increases norepinephrine synthesis by decreasing monoamine oxidase activity and increasing tyrosine hydroxylase activity. It also influences dopamine, promoting the synthesis of more norepinephrine. Finally, Estrogen stimulates brain-derived neurotrophic factor and therefore may have a neuroprotective effect.
Less is known about the role of progesterone in mood regulation than about that of Estrogen. However, like Estrogen, progesterone has receptors throughout the brain and regulates gene expression, modulates neurotransmitter systems, and activates signalling cascades. Progesterone and its metabolite, allopregnanolone, are involved in neuroprotective mechanisms, cognitive function, and mood regulation. Decreased allopregnanolone levels are associated with depression in women. It is unclear whether changes in allopregnanolone levels influence mood, or whether the body’s response to these changes does. Little is known about other progesterone metabolites and/or synthetic progesterone.
Perimenopause and Mood Swings
Perimenopause is the period preceding menopause and lasts an average of four years. The onset of perimenopause is characterised by irregular menstrual cycles or other menopause-related symptoms and culminates in 12 consecutive months of amenorrhea. With age, the hypothalamic-pituitary-ovarian axis becomes less sensitive to Estrogen, ovulation ceases to occur regularly, the follicular phase shortens, and, at times, estradiol levels in the luteal phase increase compared to those of premenopausal women. Due to these changes, women spend more time in the luteal phase and are prone to experiencing premenstrual symptoms. In later stages of the perimenopausal transition, folliculogenesis ceases, estradiol and progesterone levels decrease, and women experience amenorrhea.
Some women may experience an adverse reaction to fluctuations in hormone levels, predisposing them to depressive symptoms. A long-term study of 438 women conducted over 20 years found that the risk of depression is higher in women in perimenopause and early menopause. Depression in perimenopause may manifest differently than depression in premenopausal women. For example, sadness and irritability may be more variable during perimenopause, with women reporting lower overall heights of depression but higher levels of anger, hostility, sleep disturbances, and fatigue.
A study of 50 perimenopausal women with mild depression found that irritability is a unique symptom, separate from depression, and is associated with variability in estradiol levels. Depressive mood symptoms not only differ among perimenopausal women but are also likely to overlap with distressing menopausal symptoms such as fatigue, sleep difficulties, and decreased libido.
Risk Factors for Depression During Perimenopause
“Perimenopausal vulnerability” refers to the increased risk of developing depression in women during perimenopause and the female brain’s ability to adapt to fluctuations in Estrogen and progesterone levels during the menopausal transition. Risk factors for maladaptation include a history of main depressive disorder (MDD), which is the strongest predictor of relapse during perimenopause, as well as a past of hormone-related disposition symptoms, such as premenstrual syndrome (PMS) or premenstrual dysphoric illness (PMDD), which show a moderate association.
Both groups of women may have a genetic predisposition and vulnerability to hormonal fluctuations. An expert panel, composed of members of the North American Menopause Society (NAMS) and the Women and Disposition Disorders Task Force of the National Depression Network, reviewed the literature on depressive symptoms and disorders in perimenopausal women. The panel concluded that gloomy symptoms were more common in perimenopausal women than in premenopausal women, particularly in women with a history of major depressive disorder (MDD) (59% versus 28% in women without such a history).
The Study of Women’s Health Across the State (SWAN MHS) also found that both a personal and family history of depression or anxiety increased the risk of developing depression in women in late perimenopause or menopause.
In addition to a personal or family history of depression, unpleasant physical symptoms of perimenopause and menopause may be related with depressive symptoms. A systematic review of the association amid vasomotor symptoms and unhappiness found a statistically significant positive association in 9 of 17 studies. Still, the reviewers noted a moderate to high risk of bias.
Decreasing estrogen levels can cause adverse changes in the genitals and urinary tract in at least 50% of postmenopausal women. A retrospective cohort study found that women with vulvovaginal atrophy (VVA) had higher rates of anxiety, depression, and major depressive disorder (MDD) compared to women without VVA, particularly in women aged 45 to 54 years.
Finally, the study revealed that women with two or more adverse childhood experiences (e.g., abuse, neglect, or other trauma) had a higher risk of developing major depressive disorder (MDD) over their lifetime and MDD during menopause, compared to women without such experiences. Furthermore, if two or more adverse events happened after puberty, there was an increased risk of developing MDD during menopause, but not lifetime MDD, compared to women without such events.
The authors hypothesised that neurochemical and behavioural changes occur when adverse events occur during periods of fluctuating estradiol levels. Similarly, subsequent hormonal fluctuations during perimenopause increase the risk of developing MDD.
In addition to biological risk factors, there are psychosocial and health-related risk factors for the development of depression during perimenopause and menopause. These may include, but are not incomplete to, physical inactivity, sleep disturbances, and chronic pain.
Physical limitations, loneliness, low income, low educational attainment, and being a member of a minority group. Perimenopausal women may also face unique additional stressors, such as caring for ageing parents and dependent children, changes in marital status, and/or health challenges in midlife.
Detection and Assessment
Measuring hormone levels in perimenopausal women experiencing mood changes is not recommended. Research on estrogen levels and related symptoms in perimenopausal women is limited. Due to the variability of hormone levels, daily sampling throughout the menstrual cycle would be ideal, but this may be impractical, and the information obtained might not apply to all women. Furthermore, the issue may be the individual response to changes in hormone levels, rather than a specific value.
The best way to identify depressive symptoms is to interview all perimenopausal women, keeping in mind that women with a personal or family history of depression or a history of PMS or PMDD are particularly vulnerable.
In addition, the nurse should inquire about everyday stressors in middle-aged women, including their perception of menopause. Unfortunately, there is no specific screening tool for depressive symptoms in perimenopause or menopause. One screening option is the PHQ-9, a self-report questionnaire to identify depression.
However, common troublesome symptoms of menopause, such as difficulty sleeping or concentrating, can skew the results. An example of a more menopause-specific screening tool is the Utian Quality of Life Scale (UQOL), a self-report instrument to assess quality of life during menopause, including emotional quality of life. However, it also has limitations, as it does not distinguish between major unhappiness and depressive symptoms.
Treatment Options
Cognitive Behavioural Therapy
Cognitive behavioural therapy (CBT) is effective in treating depression in the general population, both individually and in groups. Although there are no studies examining its efficacy in treating depressive symptoms in perimenopausal women, it is still recommended due to its benefits and low risk. The goal of CBT is to help women recognise and modify thoughts that may contribute to depression, as well as to implement behavioural interventions. These positive effects have been shown to persist for a year or more after the completion of therapy.
Selective Serotonin Reuptake Inhibitors/Serotonin-Norepinephrine Reuptake Inhibitors
At any reproductive stage, including perimenopause, first-line treatment for major depressive disorder includes antidepressants and behavioural psychotherapy. Selective serotonin reuptake inhibitors (SSRIs) increase synaptic serotonin levels. Serotonin-norepinephrine reuptake inhibitors (SNRIs) increase levels of serotonin, norepinephrine, and dopamine by blocking the proteins that reuptake these neurotransmitters. The European Menopause and Andropause Society (EMAS) recommends starting with an SSRI for the treatment of depressive symptoms in perimenopausal and menopausal women, but if the response is insufficient after one month, switching to an SNRI. However, both SSRIs and SNRIs are effective and well-tolerated at usual doses. If a person with a history of depression has previously responded to a specific antidepressant, that medication should be prescribed. To date, only desvenlafaxine, an SNRI, has been studied and shown to be effective and well-tolerated in perimenopausal and menopausal women in large-scale, randomised. Placebo-controlled clinical trials.
In addition to treating mood disorders, SSRIs and SNRIs offer potential added benefits for perimenopausal women. These medicines are prescribed off-label for the treatment of vasomotor symptoms. They should not be confused with paroxetine 7.5 mg, the only non-hormonal medicines approved by the U.S. Food and Drug Management (FDA) specifically for the treatment of vasomotor symptoms, rather than depression or anxiety. SSRIs and SNRIs may also help improve sleep, an goodlooking benefit for perimenopausal women who may experience sleep difficulties.
A meta-analysis of seven studies examined the care and efficacy of antidepressants for the treatment of sleep disturbances in perimenopausal and menopausal women. The authors concluded that serotonergic antidepressants are effective in improving sleep in women. Regardless of a diagnosis of major depressive disorder or the presence of vasomotor symptoms.
Hormone Therapy for Menopause
Due to the correlation amid estrogen and progesterone and mood regulation. Menopausal hormone therapy (MHT) may be another treatment option for depression in perimenopausal women. According to the 2022 NAMS statement. In women less than 10 years post-menopause or under age 60, the benefits of MHT likely outweigh the risks. The statement notes that FDA-approved indications include vasomotor symptoms, prevention of bone loss, premature hypoestrogenism, and urogenital symptoms. However. It notes that there is some evidence that estrogen therapy may have an antidepressant effect in perimenopausal women. But not in postmenopausal women. Furthermore, estrogen therapy may improve mood and enhance the clinical response to antidepressants.
Research supports the efficacy of MHT in treating depressive symptoms. In one study. Researchers concluded that women with a history of major depressive disorder exhibit variable mood and neural replies that have not adapted to lower estrogen levels during perimenopause and menopause. And could benefit from estradiol supplementation. Conversely. Women without a history of major depressive disorder successfully adapted their brain activity and might experience a negative stress response to estradiol supplementation.
Additionally, Estrogen was effective in improving mood even after treatment of bothersome perimenopausal symptoms. One study concluded that estradiol and progesterone help prevent depression. Regardless of the treatment of vasomotor symptoms in the early stages of the menopausal transition. Researchers attributed this beneficial effect to reduced variability and decreased estradiol levels. Another study likened the possessions of estradiol, raloxifene, and a phytoestrogen in perimenopausal women with despair. Neither raloxifene nor rimostil (an isoflavone extract from red clover) improved mood or cognitive function. Although estradiol also did not improve cognitive function, it did improve mood, even after accounting for improvements in sleep.
In combined hormone replacement therapy (HRT), progesterone is prescribed as an anti-estrogen to prevent endometrial hyperplasia. However, if Estrogen is contraindicated, progesterone alone may be prescribed. A systematic appraisal of seven randomised controlled trials examined the use of progesterone for the treatment of bothersome menopausal symptoms. Including mood changes. Of these, only four studies examined progesterone treatment for mood changes, and none demonstrated its efficacy. The authors added the caveat that the most extensive study excluded women with a mood score greater than 10 on the Greene Menopausal Symptoms Scale (GMSS) and that participants were between 0 and 20 years postmenopausal.
Finally, perimenopausal women who do not wish to conceive require contraception until menopause. Hormonal contraceptives may help treat abnormal uterine bleeding and vasomotor symptoms; however. Although there are combined oral contraceptives approved by the FDA for the treatment of premenstrual dysphoric disorder (PMDD). No randomised or open-label clinical trials have been published on hormonal contraception for the treatment of women with depression.
Conclusion
When considering treatment options for depressive symptoms or relapse of major depressive disorder (MDD). SSRIs or SNRIs may be considered as first-line therapy. If the patient has previously responded favorably to a specific antidepressant, this may be chosen as initial treatment. Additionally, if the patient also presents with vasomotor symptoms. SSRIs and SNRIs may be effective. But if there are concerns about SSRI or SNRI side belongings, such as weight gain or sexual dysfunction. Hormone replacement therapy (HRT) should be considered. HRT is the gold standard treatment for vasomotor symptoms.
But there is evidence that it is also effective for depressive symptoms. With any treatment, the patient should be monitored for four weeks to assess efficacy and side effects. If some improvement is observed by then, but depressive symptoms persist. An SSRI/SNRI should be prescribed in combination with hormone replacement therapy (HRT). Estrogen has a synergistic effect with serotonin. And studies have shown an even greater impact when both medications are used simultaneously.