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Summary

Perimenopausal mood instability (PMI): ≤68% of women in perimenopause experience PMI; estrogen is an effective treatment; patients typically feel anxious, irritable, and moody, have insomnia and hot flashes, and have difficulty concentrating at work; differentiation between depression and hormonally driven mental health issue is crucial; perimenopausal women in mid 40s have multiple symptoms; prevalence is ≤80% of women in their late 40s or early 50s

PMI vs depression: in PMI, 100% of individuals report irregular periods, 80% have hot flashes, and a vast majority have urinary or vaginal symptoms; common symptoms of both PMI and major depression include sexual and weight disturbances, memory changes, and brain fog

Etiologyof PMI: explained based on the biopsychosocial model; neurotransmitters in the brain, primarily norepinephrine, dopamine, and serotonin, are involved in the regulation of mood and anxiety; estrogen and progesterone interact with brain neurotransmitters; estrogen modulates norepinephrine and serotonin; depression symptoms in perimenopause are likely related to fluctuations in the levels of estrogen and progesterone; women are protected from some forms of psychosis because of the protective effects of estrogen; progesterone targets areas of the brain that are similar to those targeted by antianxiety, sleep, and pain medications, and has calming and sleep-promoting effects in postmenopausal women; hormone levels fluctuate rapidly during perimenopause, causing symptoms of PMI; the hallmark of PMI is fluctuating mood symptoms (eg, irritability, low mood, tearfulness, decreased energy)

Major depressive disorder: 25% of women may experience major depression at some point in their perimenopause-to-menopausal transition and have twice the risk for new-onset depression, even if they have no history of depression; Patient Health Questionnaire-9 is used to differentiate depression from PMI; diagnosis is positive if a patient has ≥5 symptoms in the past 2 wk; the patient may be categorized as having mild, moderate, severe, and very severe depression

Generalized anxiety disorder (GAD): often mimics PMI in the perimenopausal period; hot flashes may feel like a panic attack, with increased sweating and heart rate; the GAD-7 score is used to diagnose GAD as well as severity

Guidelines for treatment of perimenopausal depression (PMD): Maki et al (2018) — there was no difference in the presentation of depression, but it was complicated by the presence of perimenopausal symptoms; antidepressants were equally effective in managing women with PMD of all ages; estrogen was effective for treatment of PMI in perimenopause but not in the postmenopausal period; 45% to 68% of perimenopausal women may report symptoms of PMD, with increased prevalence among Hispanic women; multiple psychological and sociocultural factors affect the risk; hysterectomy and premature ovarian insufficiency were associated with increased risk for PMD

Psychological therapy: cognitive behavior therapy (CBT) is the most effective therapy for anxiety, depression, and insomnia; evidence demonstrates benefit for management of hot flashes; specific CBT approaches exist for insomnia; CBT can be performed with mindfulness; mindfulness involves observance of one’s thoughts, feelings, and emotions without becoming emotionally attached to them; CBT identifies cognitive distortions and helps evaluate thought content and recognize when one starts to exhibit catastrophizing behavior; CBT is effective for insomnia because it helps replace ruminative thoughts that keep the individual awake; mindfulness techniques (eg, paced breathing) are effective for depression and PMI; however, paced breathing is not effective for hot flashes

Pharmacotherapy for PMI: estrogen is effective for management of PMI in the perimenopausal period but is not approved by the US Food and Drug Administration to treat PMI; estrogen use causes mood stability and improvement in low mood; it can be administered as hormone therapy alone or as part of continuous oral contraception (symptoms tend to recur in pill-free intervals)

Comorbid depression and/or anxiety and PMI: patients with coexisting PMI and major depression require treatment for symptoms of PMI; progestins help to improve sleep; exercise is recommended for improvement of sleep, hot flashes, and mood; first-line therapy for moderate or severe depression is antidepressants, ie, selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs); medications are most effective in combination with psychotherapy; start with a small dose and inform patients of adverse effects (eg, sweating, insomnia); symptoms generally improve in a few weeks; patients with PMI and mild depression or anxiety benefit from estrogen therapy; estrogen therapy is recommended for early menopause, premature ovarian insufficiency, or surgical menopause, and should be given until the average age of menopause; estrogen is not indicated for postmenopausal depression in the absence of other symptoms

General antidepressants: only desvenlafaxine (Khedezla, Pristiq) has a randomized controlled trial for use in menopause-related mood disorders; some agents promote drowsiness and have a calming effect (eg, paroxetine [Brisdell, Paxil, Pexeva], venlafaxine [Effexor]), whereas others may be activating (eg, sertraline [Zoloft], fluoxetine [Prozac, Rapiflex, Sarafem]); it is recommended to use antidepressants according to patient symptoms; bupropion (eg, Aplezin, Budeprion, Wellbutrin) does not possess any sexual adverse effects; advise avoidance of caffeine with bupropion and recommend intake during the day as it may interfere with sleep if taken at night

Methods of hormone delivery: include transdermal estrogen with oral progestin or an intrauterine device (eg, Liletta, Mirena, Skyla), and oral contraception; vasomotor symptoms may improve in 3 wk; transdermal estradiol has ≈25% the strength of an oral medication, ie, it might be insufficient to provide cycle control or contraception; oral contraception is recommended in individuals requiring contraception or cycle control

Contraindications to postmenopausal estrogen: include active liver disease, breast cancer or other hormone-dependent cancer, and personal history of heart attack, stroke, or venous thromboembolic event; family history of breast cancer, heart attack, stroke, and migraine with aura are not contraindications for estrogen use; SSRIs, SNRIs, or gabapentin are recommended for individuals who do not prefer estrogen

Duration of hormone therapy: based on risk vs benefit analysis and shared decision-making with patient