Perimenopausal Depression – A Review of Diagnosis and Management

PREVALENCE

Perimenopause is a vulnerable period for developing depression, and the risk is elevated even with no prior history of major depressive disorder. [Lin et al., 2013]

The risk of perimenopausal depression is linked to a complex interplay between hormonal vulnerability, psychosocial resources (coping skills and social support), overall well-being (exercise and other lifestyle factors) and stressful life events. [Gibbs et al., 2012]

Most published studies on the relationship between perimenopausal symptoms and depression included women between the ages of 40 and 60 from various socio-cultural and economic backgrounds. [Maki et al., 2018]

Women experiencing spontaneous or iatrogenic menopause before 45 years and particularly before 40 years are at higher risk for cardiovascular disease and osteoporosis. They may be at increased risk of affective disorders and dementia. [Baber et al., 2016]

One study showed that premenopausal women with no lifetime history of major depression who entered perimenopause have a higher risk of depression (nearly twice as likely) than women with no history of depression who remained premenopausal. [Cohen et al., 2006]

Studies were inconclusive about whether there is an increased risk in women who progress naturally through menopause instead of those with depression who reach it early.

Approximately 45% to 68% of perimenopausal women report elevated depressive symptoms compared with 28% to 31% of premenopausal women. [Brown et al., 2009], [Timur & Sahin 2010]

Elevated depression symptoms were reported among 28% to 47% of women during early menopause, and the odds of experiencing elevated depressive symptoms in this phase were higher than during the premenopausal stage. [Bromberger et al., 2004].

Women who have had a hysterectomy with or without oophorectomy are at increased risk of depression and those with primary ovary insufficiency [Darwish et al., 2014].

As expected, the risk of developing depression during menopause is highest among those with previous mental health problems, previous antidepressant use, previous pre-menstrual symptoms, e.g., night sweats, anxiety and sleep disturbances, young, black women, financial hardship and those lacking social support. [ESHRE 2016]

PHYSIOLOGY OF MENOPAUSE - ENDOCRINE CHANGES

• There is no definitive hormone marker of menopausal transition or final menstrual period.

The menopausal transition is characterised by:

• Marked decline in ovarian follicle numbers.
• Decrease in early cycle inhibin B and anti-Mullerian hormone (AMH) levels.
• The luteal phase inhibin B levels become low before the number of responsive follicles has decreased. This allows FSH levels to rise and results in endogenous perimenopausal ovarian hyperstimulation.
• This hyperstimulation results in the clinical features of the syndrome, which may include breast tenderness and enlargement, fluid retention, heavy, prolonged, or unpredictable menstrual bleeding, new onset of migraine headaches, and new or unpredictable mood swings. [Jerilynn, 1998]
• FSH increases maintain estradiol (E2) concentrations until late in reproductive life.

Post-menopause:

• FSH levels are markedly raised, E2 levels are low, whereas inhibin B and AMH are undetectable. [Burger et al., 2007]
• Since estrogen and progesterone play a significant role in many CNS processes such as modulating dopaminergic and serotonergic transmission, neuroprotection, neurogenesis, inflammation, etc., these hormones’ changes can significantly affect mood. [We covered the role of estrogen and progesterone on the brain in more detail in the article – Is the Oral Contraceptive Pill Associated with Depression?- A Synopsis of The Impact of OC Pills on Mood]
• Estrogen and progesterone also interact with the HPA axis, perturbations of which are closely linked to the pathogenesis of depression.

CLINICAL FEATURES OF PERIMENOPAUSAL DEPRESSION

Clinical Features in Perimenopausal Depression:  [Kulkarni et al., 2018]

Perimenopausal depression is characterised by typical depressive symptoms alongside menopause-specific indicators, including sleep disturbance, weight changes, lowered energy and libido and cognitive shifts. [Cohen et al., 2006], [Woods et al., 2008]

Symptoms include:

• Low energy
• Paranoid thinking
• Irritability or hostility
• Decreased self-esteem
• Isolation
• Anxiety
• Somatic symptoms
• Sleep disturbance
• Weight gain
• Decreased sexual interest
• Problems with memory and concentration

Mood:

• Mood swings can be common during menopause [Freeman et al., 2008], and psychosocial stressors can also adversely impact mood. [Woods et al., 2008], [Woods et al., 2016]
• Mood symptoms consist of anger, irritability, and paranoia, which may manifest as out of character verbal outbursts often over minor stressors. They occur as an on-off phenomenon lasting for mins to a few hours and then spontaneously resolve.
• Depressive symptoms are closely linked to several menopausal symptoms (nocturnal hot flashes, sleep disturbance, irritability, muscle stiffness, and incontinence). Thus, menopausal symptoms may influence depressed mood through sleep disturbance. [Brown et al., 2009]

Vasomotor symptoms

Cognitive Symptoms:

• It is challenging to disentangle cognitive symptoms as both depression and menopause can impact concentration to varying degrees. [Soares, 2014]
• In longitudinal studies, slower processing speeds and worsening memory were linked to depression and anxiety during menopause.
• Midlife women may also experience concurrent coding deficits that amplify possible cognitive slowing effects. [Greendale et al., 2009]

Fatigue:

• Fatigue is commonly reported alongside other common complaints such as decreased energy, increased appetite, and compound other menopausal symptoms. [Baune et al., 2012]

Decreased libido

• It is commonly reported during menopause, but as it is also common in depression, its impact may be heightened.
• It is particularly common post-surgically. [Derogatis & Burnett 2008]

Urinary incontinence:

• In some limited studies, there is a bi-directional link between depression and urinary incontinence in women experiencing menopause, and other cross-sectional studies reported an increased risk of depression in perimenopausal women with urinary incontinence. [Cagnacci et al., 2017]

Clinicians should consider these issues carefully when trying to differentiate symptoms from one another.

ASSESSMENT AND DIAGNOSIS OF PERIMENOPAUSAL DEPRESSION

Assessment and Diagnosis

Differential diagnoses in perimenopausal depression include:

• Major depressive disorder
• Subsyndromal depression
• Bipolar disorder
• Adjustment disorders
• Bereavement
• Psychosocial stressors; Some psychosocial aspects of menopause may be unique to midlife, children leaving home, changing family structure, loss of role function postulating ’empty nest’ syndrome as a differential. The syndrome is now refuted. [Dennerstein et al., 2002]
• Medical conditions – Thyroid dysfunction, primary ovarian insufficiency, iron deficiency etc.

10 Point Visual Guide to Medical Evaluation In Mood Disorders

Women with past moderate depressive episodes (not always hormone-related) and those with severe depressive symptoms and/or suicidal ideation should always be assessed for a mood disorder.

The menopausal phase should be identified, and valid assessment tools should be used to identify psychiatric symptoms from those specific to menopause. [Maki et al., 2018]

Several validated tools such as the PHQ-9 can screen for depression.

The MENO-D rating scale developed by Prof Kulkarni is a valuable and valid tool to detect perimenopausal depression. [Kulkarni et al., 2018]

Women experiencing perimenopausal depression complain about physical symptoms more than cognitive symptoms, which are not typically included in previous scales assessing for major depressive disorder leading to an underdiagnosis or missed diagnosis.

The most common perimenopausal physical complaints are irritability (45%), headache (39.8%), body ache (34.3%), sleep disturbance (33.3%), and joint pains (35%). [Jagtap et al., 2016]

These physical aspects are captured as part of MENO-D.

Clinicians may also use quality of life questionnaires to clarify symptom types.

They include the: Menopause Rating Scale (MRS), Menopause-Specific Quality of Life Questionnaire (MENQOL), Greene Climacteric Scale, Utian Quality-of-Life Scale). [Greene, 1976], [Hilditch et al., 1996], [Utian et al., 2002]

ANTIDEPRESSANTS FOR THE TREATMENT OF PERIMENOPAUSAL DEPRESSION

Antidepressant medications, cognitive behavioural therapies and other psychological therapies remain the first-line treatments for perimenopausal depression.

• For mild depression, without suicidality, in middle-aged women, when there are some physical symptoms suggestive of perimenopausal changes, hormone therapy alone may be appropriate. [Kulkarni, 2018]
• The usual first-line medication for perimenopausal depression is SSRIs. SNRIs are often second-line medications if SSRIs are not successful in treating depression. [Kulkarni, 2018]
• SSRI and SNRIs have been shown to improve menopause-related symptoms, and remission rates were higher among older women taking SNRIs. [Thase et al., 2005]
• A meta-analysis showed that antidepressant treatment, either with SSRIs or SNRIs, was efficacious for managing depressive symptoms across the full spectrum of depressive disorders presenting during or after the menopausal transition. Antidepressant treatment during menopause was also associated with higher response and remission rates than placebo. [Wu et al., 2020]
• Antidepressants could also be efficacious for women with subthreshold depressive symptoms. However, antidepressant treatment was associated with a greater likelihood of discontinuation due to adverse events. [Wu et al., 2020]
• It is important to tailor the choice of SSRI. For example, fluoxetine can have an agitating side effect due to the 5-HT2C antagonism; therefore, a woman with prominent insomnia, irritability and anxiety may report an exacerbation of these symptoms with fluoxetine treatment.
• Data from previous studies show that citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, venlafaxine and vortioxetine are tolerable at therapeutic doses [Maki et al., 2018], [Freeman et al., 2017], and they generally have a positive impact on sleep, anxiety and pain symptoms linked to menopause. [Ladd et al., 2005]
• Estrogen based therapies may augment and /or accelerate clinical response to antidepressants in peri-or postmenopausal women, but their use should be considered with caution. [Maki et al., 2018]
• Venlafaxine (75 mg /day), desvenlafaxine, low dose paroxetine, citalopram, escitalopram, Gabapentin (300 mg TDS), clonidine,  progesterone/ progestins are effective in reducing hot flushes in postmenopausal women. [Baber et al., 2016], [Santoro, 2016]
• Desvenlafaxine is the only antidepressant drug proven efficacious in well-defined, longitudinal studies of peri and postmenopausal women. [Maki et al., 2018]
• Agomelatine is a newer antidepressant with a positive sedative impact and fewer adverse effects in women with perimenopausal depression. Agomelatine significantly improved depression, anxiety, irritability and disordered sleeping. In addition, it had a positive impact on physical symptoms  (particularly hot flashes, decreased performance, sexual problems, and joint/muscle pain). [Krüger & Tran, 2014]
• Where major depressive disorders occur midlife in women previously diagnosed with major depression, treatment selection should always be guided by previous treatment responses, including prior trials, tolerability and impact on challenging adverse effects such as weight gain and sexual dysfunction. [Maki et al., 2018]
• The safety of drug-drug interactions is also essential, given that other medications will likely be prescribed or self-prescribed. e.g. Tamoxifen and SSRIs; SSRIs can attenuate tamoxifen efficacy in treating breast cancer via CYP2D6 inhibition. Fluoxetine, duloxetine, bupropion, and especially paroxetine are potent CYP2D6 inhibitors. Citalopram, Escitalopram and Sertraline are less likely to interact. Pharmacogenomics and Drug Prescribing (Genetically Guided Prescribing) in Psychiatry – The Current State of Evidence
• Co-morbid sleep disturbance and night sweats should also be part of one’s treatment plan for menopausal depression. [Maki et al., 2018]

HORMONE REPLACEMENT THERAPIES | MENOPAUSAL HORMONAL TREATMENT

Previously termed hormone replacement treatment (HRT); Menopausal hormone treatment (MHT) with or without progesterone exerts beneficial effects on mood during the menopausal transition and early postmenopausal periods. [Gleason et al.,2015]

Menopause hormone treatment (MHT) should always be implemented as part of an overall strategy, with lifestyle recommendations regarding diet, exercise, smoking and alcohol to improve general health status. 

Early assessment and management of depression symptoms during menopause are therefore desirable. [Maki et al., 2018]

Estrogen therapy

• Evidence suggests that estrogen therapy (estradiol) is not effective for postmenopausal women, but it may improve mood and well-being in perimenopausal women without depression. [Maki et al., 2018]
• Estrogen therapy has similar effects to antidepressant medications when given to depressed perimenopausal women with or without comorbid vasomotor symptoms.
• Compared to placebo, transdermal estradiol (0.05 mg/day) improved depression scores significantly after 3 weeks in perimenopausal depressed women  (0.05 mg/day). [Schmidt et al., 2000]
• After 12 weeks, depressive disorders in perimenopausal women were significantly more likely to remit with transdermal estradiol (0.1 mg/day) than placebo. [Soares et al., 2001]
• Estrogen has not been FDA approved for the treatment of mood disturbance but may be appropriate to prescribe in healthy women without suicidality. [Schneider et al., 2001]

Combined estrogen and progesterone: 

• A large 4-year study reported that Conjugated equine estrogens (CEE) (0.45 mg/day, with cyclic progesterone 200mg daily for 12 days) but not transdermal estradiol (0.05 mg/ day, with cyclic progesterone 200mg daily for 12 days) improved depressive symptoms (but not cognitive symptoms) compared to placebo.
• In perimenopausal women, hormonal contraceptives yielded many benefits, including restoring menstruation, reducing heavy bleeding and dysmenorrhoea, and treating vasomotor signs. [Allen & Cwiak, 2016]
• However, most studies on hormone therapy for the treatment of depression involved estrogen alone, and data on estrogen combined with progesterone were inadequate.

Recommendations: [Stevenson, et al, 2020]

• In newly menopausal women, a sequential MHT regimen (daily estrogen with a progestogen for 12–14 days/cycle) is appropriate. Regular progestogen withdrawal bleedings (i.e. monthly menses) will occur.
• Women who have been postmenopausal for at least a year or those with weak or absent withdrawal bleeds can be switched to a continuous (daily) combined estrogen/progestogen regimen.
• Micronized progesterone and dydrogesterone appear to be the safest options for minimising cardiovascular, thromboembolic, and breast cancer risks compared with other progestogens.

Tibolone (selective estrogen activity regulator): 

• Tibolone is a synthetic steroid selective tissue estrogenic activity regulator that has shown benefits in treating perimenopausal depression. [Kulkarni et al., 2018]
• Tibolone shows estrogenic effects in the brain, vagina, bone and cardiovascular system.
• In the endometrium, the progestogenic activity of the Delta-metabolite and the effect on oestrogen-inactivating enzymes prevent estrogenic stimulation.

Oral Estrogen plus Selective Estrogen Receptor Modulator (SERM): Tissue-Selective Estrogen Complex (TSEC)

• Bazedoxifene is a third-generation selective estrogen receptor modulator (SERM) that has a antiestrogenic effect on the endometrium. It is used for osteoporosis management in postmenopausal women that are at risk of fractures.
• The Tissue-Selective Estrogen Complex (TSEC) combines bazedoxifene and conjugated estrogens and is designed not only to improve menopausal symptoms and vulvovaginal atrophy but also to prevent bone loss. Therefore, it maintains the benefits of estrogen therapy while antagonising the stimulation effects on the endometrium and mammary gland without the effects associated with progestins. [Palacios & Mejía Ríos, 2015]. 

Combined Antidepressant and hormone treatment : 

• Combining hormone therapy and antidepressant therapy may be required for perimenopausal women with depressive symptoms that do not respond to either treatment alone.

Preventative treatments

• In terms of preventative treatment, there is insufficient evidence around estrogen-based therapies for asymptomatic patients. [Maki et al., 2018]
• Only one randomised trial has studied hormone replacement therapy for the prevention of depression during early postmenopause, showing that preventative transdermal estradiol (0.1mg/day) plus oral micronised progesterone (200mg/day for 12 days every 3 months, may augment clinical antidepressant response in midlife and older women, particularly when vasomotor symptoms are also present. [Gordon et al., 2018]

Important points in MHT use:[Kulkarni, 2018], [Baber et al., 2016]

ALTERNATIVE THERAPIES FOR PERIMENOPAUSAL DEPRESSION

• Exercise may benefit peri- and postmenopausal women with depression, particularly if they are proposed alongside other recommended psychotherapies and pharmacotherapies. [Maki et al., 2018]
• For women who prefer not to use medication to treat perimenopausal depression, a range of cognitive-behavioural, behavioural, and mindfulness-based therapies have been found effective in reducing the severity of symptoms, especially cognitive-behavioural therapy (CBT). [Green et al., 2015]
• Of these non-pharmacological trials, CBT appears to have demonstrated the most beneficial effect and has been found to reduce depressive symptoms by at least 50% for half of the participants and achieve complete remission for just over 25% of participants. [Brandon et al., 2013]
• Botanical or complementary/alternative medicines for treating perimenopausal depression are not advised because there is a paucity of valid studies. [Maki et al., 2018]

• HRT vs Antidepressants in Perimenopausal Depression By Prof Jayashri Kulkarni
• Hormones and Mental Illness in Women – PMDD / Depression and the Pill / Perimenopausal Depression- Prof Kulkarni
• Tibolone As Adjunctive Treatment in Perimenopausal Depression By Prof Jayashri Kulkarni

SUMMARY

Women experiencing menopause are at greater risk of developing depression and major depressive episodes.

Symptoms often mirror those of classic depression, and many occur alongside menopause symptoms (i.e., vasomotor symptoms, sleep disturbance, anxiety), complicating existing depression or clouding initial diagnosis.

Co-occurring psychiatric and menopause symptoms should be assessed using valid, evidence-based screening tools, and psychosocial factors common to midlife women should be considered.

Particular attention should be paid to those at higher risk of developing menopausal depression, including lower socio-economic groups, ethnicity, previous mental health problems, increased social stressors, or lack of familial or social support. [Maki et al., 2018], [Stute et al., 2020]

Proven first-line treatment options for depression include antidepressants and psychotherapy.

Lifestyle changes may also be appropriate for minor to moderate symptomatologies. [Maki et al., 2018], [Stute et al., 2020]

Although estrogen therapy is not approved to treat perimenopausal depression, evidence shows that it has antidepressant effects in perimenopausal women, particularly those with coexistent vasomotor symptoms.

Data on estrogen plus progestin are sparse and inconclusive, so further research is needed. [Maki et al., 2018], [Stute et al., 2020]

Most women with perimenopausal depression respond to treatment. It is important to recognise the special symptoms of perimenopausal depression as well as the serious nature of this depression. Clinicians need to provide a tailored management approach for these women. It is not appropriate to deem this type of depression as minor or presume that, once the hormonal fluctuations settle, the depression will improve. The process of menopause can take many years, during which the patient’s quality of life and that of her family, may deteriorate irreparably. Tragically, suicide in middle-aged women is becoming a more common occurrence. [Kulkarni, 2018]