Perimenopausal depression refers to the specific pattern of depressive symptoms that can emerge during the menopause transition1 and is a distinct subtype of major depressive disorder (MDD) with a hormonal aetiology.2 It is not recognised in psychiatry classification systems.
Psychological symptoms are often early signs of perimenopause and are caused by neurochemical and neurocircuitry changes due to gonadal hormone fluctuations in the central nervous system (CNS).3
Hormonal mood disorders
Women are born with a finite ovarian reserve that is typically depleted between the ages of 40 and 55 years. Menopause is defined as the cessation of menstrual periods for 12 consecutive months. The next phase is postmenopause, characterised by low levels of estradiol and progesterone.
Perimenopause may begin 10 years earlier than menopause, with fluctuating estradiol, declining progesterone, more anovulatory cycles and gradual testosterone decline. This hormonal ‘zone of chaos’ can profoundly affect the brain and trigger new or recurrent mental illness, especially in women sensitive to hormones (Figure 1).
Women are at increased risk of perimenopausal depression if they have a history of hormone-related mood disorders4 such as postnatal depression (PND), which affects 15% of women,5 or premenstrual dysphoric disorder (PMDD; occurs in 5–8% of women).6 Mood-related side effects occur in 20–30% of women using hormonal contraception.7
Figure 1. Schematic of gonadal hormone fluctuations in mid to later life in women.
Neuroscience of hormonal mood disorders
Estradiol, progesterone and testosterone regulate key neurotransmitters: serotonin, dopamine, glutamate and γ-aminobutyric acid (GABA), which influence mood and cognition.
Estradiol has a brain-activating effect by modulating glutamate, serotonin and dopamine, driving energy, mood and cognitive functioning. Progesterone and its metabolite allopregnanolone are calming, modulating GABA8 to promote sleep and reduce anxiety. Emerging evidence supports testosterone’s role in mood and cognition.9
Gonadal hormones enhance synaptic plasticity,10 playing a key part in neurocircuitry development, which is essential for learning and higher cognition.10
Hormonal fluctuations disrupt serotonin and dopamine receptor expression, which are critical for maintaining mood stability.11,12 Reduced brain oestrogen may lead to cognitive decline and emotional dysregulation in menopausal women.13
Symptoms and risk factors for perimenopausal depression
Perimenopausal depression is unlike MDD, which is characterised by persistent low mood. The early symptoms of perimenopausal depression include fluctuating anxiety and agitation, followed by intermittent anhedonia, low libido, social withdrawal, cognitive issues (‘brain fog’) and episodic rage.2,14 Physical symptoms include weight gain, joint pain, fatigue and low energy.14 Symptoms can vary dramatically from week to week. The treatment for perimenopausal depression needs to be different from MDD treatment and requires the consideration of hormone therapy.1,2
Risk factors include a history of mood disorders, prior hormonal mood disorders (PMDD, PND),5,6 early or surgical menopause15 or primary ovarian insufficiency,16 neurodivergence (attention deficit hyperactivity disorder [ADHD] and/or autism – more often undiagnosed in females),17 childhood trauma18 and living with family violence.19
Diagnosing perimenopausal depression
Perimenopausal depression is difficult to diagnose and is frequently identified retrospectively, after the onset of hot flushes and amenorrhoea. Hence, perimenopausal mental ill health is often incorrectly diagnosed, inappropriately treated or missed altogether.20
There are no definitive biological tests to objectively diagnose perimenopause or perimenopausal depression. Estradiol and progesterone levels are usually normal in perimenopause, and follicle-stimulating hormone rises following consistent non-ovulation, which occurs late in the menopause transition.11
To assist clinicians and women to understand, diagnose and quantify perimenopausal depression, the Meno-D rating scale was developed (Appendix 1, available online only).21
The Meno-D is an interviewer- or self-rated scale assessing 12 typical symptoms: low energy, paranoid thinking, irritability, self-esteem, isolation, anxiety, somatic symptoms, sleep disturbance, weight, sexual interest, memory and concentration, scored from 0 (not present) to 4 (severe).
The total score (out of 48) assists in categorising severity and guiding management of perimenopause depression:
- 20–24 = mild; treatment optional, ongoing monitoring required
- 25–32 = moderate; treatment indicated
- >32 = severe; urgent treatment required.
The Meno-D is easily accessible and available in multiple languages, and it can also be used to monitor progress with treatment.
Excluding other mood disorders
Perimenopausal depression can resemble bipolar type 2, unipolar depression, undiagnosed ADHD or complex post-traumatic stress disorder, and it may also co-exist with them.20 Differentiation requires thorough assessment. Organic causes and substance use, including alcohol, can mimic or compound symptoms.
Treatment for perimenopausal depression
Hormone therapy should be the first-line treatment for new-onset perimenopausal depression (Figure 2). It is more effective than antidepressants, which carry significant side effects and withdrawal risks.22 Women in this stage often respond poorly to antidepressants.23
Figure 2. Perimenopausal hormone treatment decision tree.
Bi-MHT, body-identical menopausal hormone therapy; COCP, combined oral contraceptive pill; IUD, intrauterine device; Meno-D, Menopause Depression Rating Scale; PV, vaginally.
Many women and healthcare professionals are still concerned about the 2001 Women’s Health Initiative (WHI) study that sensationally implied that menopause hormone therapy (MHT) caused breast cancer and strokes.
24 Reappraisal of WHI data showed a decreased incidence of breast cancer with oestrogen treatment alone, and the small breast cancer risk was associated with medroxyprogesterone in the combination MHT arm.
25 The Australian Menopause Society (AMS) provides further information.
26
Body-identical hormones, especially transdermal estradiol plus micronised progesterone, are safe for most women, with no evidence of increased breast cancer risk27,28 or venous thromboembolism.29
The goal of MHT in perimenopausal depression is to stabilise fluctuating gonadal hormone levels.3
MHT oestrogen
Estradiol is lipophilic, allowing it to cross the blood–brain barrier and improve mood and cognition.3 Conjugated oestrogens and hemihydrate salts cross less effectively, making 17β-estradiol a more potent option for depression. If using hemihydrate gel (eg Estrogel), higher doses may be needed for mental health benefits.30 The AMS dose equivalent guide is an important resource.26 As an activating hormone, estradiol is best taken in the morning.
MHT progesterone
Continuous combined regimens, when appropriate, help stabilise hormonal fluctuations. Micronised progesterone is the safest option and improves sleep and mood,31 so it may additionally benefit women with a hormonal intrauterine device (IUD) or post hysterectomy.
Some women are susceptible to progestins, which cause increased depression and anxiety.32 The older progestins (medroxyprogesterone, dydrogesterone, levonorgestrel, norethisterone) tend to worsen mental illness in sensitive women. This heightened sensitivity can also occur with the levonorgestrel IUD.32
While more common with synthetic progestins, micronised progesterone can also worsen anxiety or depression. If so, using micronised progesterone vaginally can reduce CNS exposure.33
Testosterone
Although testosterone is licensed for postmenopausal hypoactive sexual desire disorder, emerging evidence suggests benefits for transdermal testosterone treatment in mood and cognition in perimenopause.9 Testosterone treatment with AndroFeme 1 (0.5 mL daily) takes up to 3–6 months to have an effect and needs monitoring.34
Other hormone therapies
For women requiring contraception, the combined oral contraceptive pill Zoely, containing nomegestrol and estradiol, is mood neutral.7 Unless problematic intermittent bleeding occurs, it can be taken without the placebo pills for three cycles to stabilise gonadal hormones.
For women in their late 40s and early 50s with perimenopausal depression, tibolone is a useful activating synthetic steroid with oestrogenic, progestogenic and androgenic effects. Tibolone can lead to intermenstrual bleeding, but can treat perimenopausal depression.35
If tibolone’s impact ceases or declines, then standard MHT for women in their mid‑50s onwards becomes an important perimenopausal depression treatment.
Antidepressants
Women already taking antidepressants who develop worsening mental illness at midlife should continue their current antidepressants. Where suicidal ideation is present, consider prompt psychiatrist referral.2
The Therapeutic Goods Administration currently approves no medications for perimenopausal depression; MHT, contraceptives and antidepressants are used off-label.
Over-the-counter medications
Many women use over-the-counter or naturopathic hormone products. It is essential to discuss these openly, considering ingredients, poor evidence for efficacy, costs and potential interactions.
Non-pharmacological intervention
Psychotherapy may be needed for coexisting stressors, especially trauma-targeted therapy such as eye movement desensitisation and reprocessing36 for women with early life trauma experiencing resurgence of symptoms at perimenopause.
Partners and family also need assistance and education to support the woman through menopause transition.
Healthy lifestyle advice about nutrition, exercise, social connection, meditation, cognitive therapies, smoking cessation, alcohol and other drug use such as cannabis minimisation should accompany treatments for perimenopausal depression.
Approach in primary care
The key, as always, is listening. Up to 80% of women experience psychological symptoms, including resurgence of trauma-related symptoms, in perimenopause, so maintaining broad clinical awareness is critical.
It is important for GPs to watch for women aged in their early 40s with new-onset mental illness or relapse of previously stable mood disorders. Other red flags include mood fluctuations, history of hormonal mood symptoms or coexisting menopause symptoms.
The new Medicare Benefits Schedule menopause and perimenopause health assessment item number (695)37 and the 45–49 health assessment item numbers (703–707) can be used; these allow the involvement of a practice nurse.
The Healthy Hormones HOT FLUSH acronym offers a practical guide (Figure 3) to approaching perimenopause consultations.
Figure 3. Mnemonic for managing hot flushes.
BP, blood pressure; DEXA, dual-energy X-ray absorptiometry; PMDD, premenstrual dysphoric disorder; PMS, premenstrual syndrome; PND, postnatal depression; USS, ultrasound scan.
Complex cases often require collaboration with psychologists, psychiatrists and menopause specialists. Perimenopausal depression is associated with suicide,
38 hence the condition needs early identification and appropriate treatment. Reputable resources about menopause are available for clinicians and non-clinicians (Table 1).
| Table 1. Key clinical resources for perimenopause care |
| Organisation |
Description |
Website |
| Healthy Hormones |
A free, general practitioner–led community for health professionals, offering menopause resources, webinars, courses, events, networking and a forum for case discussions. A separate public platform supports patients. |
www.healthyhormones.au |
| Australasian Menopause Society |
Evidence-based resources for health professionals and the public regarding menopause and midlife, with an annual scientific meeting. |
www.menopause.org.au |
| Jean Hailes for Women’s Health |
A not-for-profit organisation providing education, research and clinical resources on women’s health across the life course. |
www.jeanhailes.org.au |
| International Menopause Society |
A multidisciplinary organisation supporting health professionals worldwide through evidence-based guidelines, position statements, educational resources and biennial congresses. |
www.imsociety.org |
| HER Centre Australia |
An Australian initiative dedicated to advancing research, education and clinical care in reproductive and hormonal health. It provides evidence-based resources and training for health professionals. |
www.monash.edu/medicine/her-centre |
Conclusion
GPs are the specialists in whole-person care – and perimenopausal depression demands exactly that. Driven by hormonal fluctuations, perimenopausal depression is a distinct, biologically based condition that remains under-recognised. With greater awareness, appropriate screening (eg Meno-D rating scale) and hormone-based treatment, GPs can improve outcomes for women in midlife facing work, caregiving and family demands. Ongoing education and collaboration support best practice in this complex life stage.
Key points
- Perimenopause changes begin in the brain in a woman’s early 40s.
- Perimenopausal depression is different in quality to MDD.
- MHT is effective in treating perimenopausal depression, either alone or in combination with antidepressants plus lifestyle interventions.
- A holistic, collaborative approach is needed to assist women who want help with menopause transition challenges.