SSRIs, SNRIs and Mirtazapine: Choosing the Right Antidepressant for Hormone-Sensitive Mood Disorders
Lancet 2025 paper - The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis
The new analysis by Pillinger et al. (The Lancet, 2025) reviewed over 58,000 participants across 151 randomised controlled trials, comparing how different antidepressants affect the body.
While all major antidepressant classes were effective for mood, the study revealed important differences in physiological impact, especially among SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin–noradrenaline reuptake inhibitors) and mirtazapine — one of the most commonly prescribed alternatives.
The findings have meaningful implications for women’s mental health, particularly when mood disorders arise in connection with hormonal change.
How SSRIs Compare
SSRIs remain the mainstay for hormone-sensitive mood conditions like PMDD, postnatal depression, and perimenopausal anxiety.
The Lancet analysis confirmed that, while all SSRIs share similar efficacy, their side-effect profiles vary considerably.
Sertraline, escitalopram, and fluoxetine were the most physiologically neutral, showing minimal effects on weight, heart rate, or blood pressure.
Paroxetine was associated with slightly higher weight gain and a modest increase in resting heart rate.
Citalopram and escitalopram remained among the best-tolerated overall.
These differences can guide treatment selection: for example, sertraline is often favoured for its low side-effect burden and safety in breastfeeding, while fluoxetine may suit those who prefer a more activating antidepressant during the day.
How SNRIs Compare
SNRIs, including venlafaxine and duloxetine, can be particularly effective where anxiety, tension, or chronic pain accompany low mood — all common features of reproductive mood disorders.
However, the Lancet data showed that SNRIs have a more pronounced physiological footprint than SSRIs. Both venlafaxine and duloxetine caused modest but statistically significant increases in blood pressure and heart rate, likely reflecting their noradrenaline-boosting mechanism.
In practice, this means that SNRIs can be highly effective for women with PMDD or perimenopausal anxiety, especially when irritability and fatigue dominate — but they should be used with caution in women who already experience hot flushes, elevated blood pressure, or palpitations.
Mirtazapine: A Different Option
Mirtazapine works differently from both SSRIs and SNRIs, acting on serotonin and noradrenaline receptors rather than reuptake transporters.
In The Lancet review, mirtazapine showed minimal cardiovascular effects — making it a safe option from a heart-rate and blood-pressure perspective — but it was among the most associated with weight gain and sedation.
That combination can be both helpful and challenging.
For some women with perimenopausal insomnia, appetite loss, or agitation, mirtazapine’s sedative effect can dramatically improve sleep and reduce anxiety.
For others — especially those already struggling with fatigue or weight gain linked to hormonal changes — it may be less ideal.
Clinically, I often consider mirtazapine when poor sleep, anxiety, or appetite loss are prominent, but I pair it with careful nutritional and metabolic support to minimise longer-term effects.
What This Means for PMDD, Postnatal Depression and Perimenopausal Mood Changes
PMDD
SSRIs remain the first-line option, often taken during the luteal phase only. Sertraline, escitalopram, and fluoxetine remain the gold standard.
For severe cases or those with prominent fatigue, venlafaxine or occasionally mirtazapine may be helpful alternatives.
Postnatal Depression
In postnatal depression, sertraline and escitalopram are generally preferred for their safety in lactation and low activation risk.
Mirtazapine can be particularly useful when sleep disruption, appetite loss, or marked anxiety dominate — but needs balancing against its potential to increase appetite and weight.
SNRIs are less commonly used postnatally due to their blood pressure effects but may help if anxiety is resistant to first-line treatment.
Perimenopausal Mood Disorders
During perimenopause, where fluctuating oestrogen levels often destabilise both mood and metabolism, sertraline and escitalopram offer stability without worsening weight or cardiovascular risk.
Venlafaxine can be helpful for women who also experience hot flushes, as it reduces vasomotor symptoms, but it can raise blood pressure.
Mirtazapine may help those whose primary complaint is insomnia, but careful monitoring of weight and energy is important.
Personalised, Phase-Specific Treatment
The Lancet data underscore the importance of matching the antidepressant not just to symptoms, but to the hormonal and physiological context in which they occur.
At Sirona Health, I consider:
The timing of symptoms within the menstrual or life stage
Cardiometabolic profile (weight, BP, heart rate)
Sleep and anxiety patterns
Hormonal therapy (COCs or HRT)
Breastfeeding or postpartum factors
This holistic approach ensures that antidepressant therapy supports both mental health and physical wellbeing.
The Takeaway
The Lancet 2025 analysis confirms that SSRIs, SNRIs and mirtazapine are all effective — but not all equal in their physiological effects.
SSRIs (especially sertraline, escitalopram, fluoxetine) remain the safest and most balanced options for hormone-related mood disorders.
SNRIs (venlafaxine, duloxetine) are powerful tools for anxiety and pain, but require blood pressure monitoring.
Mirtazapine offers excellent symptom relief for insomnia and agitation, though it can increase appetite and sedation.
Personalised prescribing — especially for PMDD, postnatal and perimenopausal mood disorders — allows us to combine the best of hormonal and psychological care with the right pharmacological support.
FAQ
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Sertraline, fluoxetine, and escitalopram. They’re effective, well-tolerated, and can be taken continuously or just in the luteal phase.
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Yes. Luteal-phase dosing (starting after ovulation until day 1–2 of bleeding) is an evidence-based option and often limits side effects.
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Sertraline or escitalopram are commonly chosen because they’re well-tolerated and compatible with breastfeeding (infant exposure is typically low).
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Yes—especially if anxiety, tension, or pain are prominent. They can raise blood pressure/heart rate, so monitoring is advised.
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Helpful when insomnia, agitation, nausea, or appetite loss dominate. It’s usually neutral for blood pressure but can increase sedation and weight.
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Often yes. For perimenopausal mood symptoms, an SSRI/SNRI alongside appropriately dosed oestrogen/progestogen can work well. Your clinician will check for interactions and dosing.
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Some PMDD patients improve within the first cycle on an SSRI; for continuous treatment, allow 2–4 weeks (sometimes 6) for full effect.
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Discuss switching within class (e.g., sertraline ↔ escitalopram) or to a different class (e.g., from SNRI to SSRI, or consider mirtazapine if sleep is poor). Tailoring solves most tolerability issues.
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Sertraline is often first choice; escitalopram is also used. Your clinician will individualise based on maternal/infant factors.
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Always taper with your clinician’s plan—especially with SNRIs (and paroxetine). Gradual dose reductions minimise withdrawal symptoms.